Basic Sciences

ARID1A Loss Drives ICC Development: Hepatology | June 2026

Introduction: Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary liver cancer with poor prognosis and limited treatment options. While ICC has traditionally been considered a malignancy of biliary epithelial cells, increasing evidence suggests that hepatocytes can also serve as a cell of origin. Understanding the molecular events that initiate this transformation is critical for developing targeted preventive and therapeutic strategies. Why was this study needed?: The cellular origin of ICC remains incompletely understood. Mechanisms driving hepatocyte transformation into ICC are poorly defined. ARID1A mutations are common in ICC, but their functional role in tumor initiation is unclear. Identifying early molecular events could reveal novel therapeutic targets for this highly aggressive cancer. Results: Using complementary mouse and cellular models, the investigators demonstrated that hepatocytes undergo marked hyperpolyploidization during the earliest stages of ICC development. This hyperpolyploid state promoted abnormal cell division, chromosomal instability, and malignant transformation. Mechanistically, ARID1A was identified as a key regulator that suppresses hyperpolyploidy by maintaining normal centrosomal and mitotic function. Loss of ARID1A disrupted mitotic integrity, accelerated hepatocyte hyperpolyploidization, and promoted ICC formation, establishing a direct mechanistic link between ARID1A deficiency and hepatocyte-derived cholangiocarcinogenesis. Clinical Impact: This study reshapes current understanding of ICC pathogenesis by demonstrating that mature hepatocytes can directly give rise to ICC through ARID1A-dependent genomic instability. The findings identify hyperpolyploidization as a potential early biomarker and therapeutic target, while highlighting ARID1A-deficient ICC as a biologically distinct subtype that may benefit from future precision medicine approaches targeting chromosomal instability or mitotic regulation. Bottom Line: ARID1A deficiency promotes hepatocyte hyperpolyploidization and chromosomal instability, driving the development of intrahepatic cholangiocarcinoma and providing new mechanistic insights into ICC initiation and potential therapeutic targets.

Blocking Succinate–GPR91 Signaling in MASH: Hepatology | April 2026

Introduction: Liver fibrosis is the key determinant of long-term outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Activated hepatic stellate cells (HSCs) drive fibrogenesis, but effective antifibrotic therapies remain unavailable. This study investigated whether blocking the succinate–GPR91 signaling pathway in HSCs could halt fibrosis progression. Why was this study needed? Liver fibrosis is the strongest predictor of liver-related mortality in MASH. Hepatic stellate cells are the principal drivers of fibrosis. Succinate accumulates during metabolic liver injury and activates HSCs through the GPR91 receptor. The therapeutic potential of targeting GPR91 had not been confirmed in vivo. Novel molecular targets are urgently needed to prevent fibrosis progression. Results: Blocking GPR91 specifically in hepatic stellate cells markedly reduced liver fibrosis, collagen deposition, and fibrogenic activity in experimental MASH. Succinate promoted hepatic stellate cell activation and survival, whereas GPR91 inhibition suppressed profibrotic signaling and enhanced HSC apoptosis. These findings identify the succinate–GPR91 pathway as a key driver of MASH fibrosis and a promising therapeutic target for future antifibrotic therapies. Clinical Impact: This study identifies a novel metabolic signaling pathway linking succinate accumulation to hepatic stellate cell activation and fibrosis. Targeting GPR91 could represent a new class of antifibrotic therapy capable of slowing or preventing fibrosis progression in patients with MASH. Bottom Line: The succinate–GPR91 signaling pathway is a major driver of liver fibrosis in MASH. Blocking GPR91 effectively suppresses hepatic stellate cell activation and fibrosis, making it a promising target for next-generation antifibrotic therapies.

THRSP–MIF Signaling Drives MASH Progression: Hepatology | April 2026

Introduction: The progression from metabolic dysfunction-associated fatty liver (MAFL) to metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex interactions between hepatocytes and immune cells. This study identifies a novel spatial mechanism in the periportal (PP) zone, where lipogenic hepatocytes communicate with lipid-associated macrophages (LAMs) to promote inflammation and fibrosis. Why was this study needed? The mechanisms driving progression from steatosis to MASH remain incompletely understood. Liver zonation may influence disease progression, but its role has been poorly defined. Lipid-associated macrophages (LAMs) are increasingly recognized as key mediators of fibrosis. Novel molecular targets beyond current therapies are urgently needed. Understanding cell-to-cell communication may enable precision therapies for MASH. Results: THRSP-positive hepatocytes promoted MASH progression by producing palmitic acid and recruiting CD74-positive lipid-associated macrophages through MIF signaling, particularly within the periportal region. This hepatocyte–macrophage crosstalk amplified hepatic inflammation, stellate cell activation, and fibrosis, identifying a key mechanism underlying disease progression. A novel THRSP inhibitor (C6) significantly reduced inflammation and fibrosis in experimental MASH, highlighting THRSP as a promising therapeutic target. Clinical Impact: This study provides important insight into the spatial biology of MASH, demonstrating that fibrosis is driven by localized communication between metabolically active hepatocytes and inflammatory macrophages. Targeting the THRSP–MIF–CD74 signaling axis may offer a new precision approach to prevent fibrosis progression beyond current therapies such as resmetirom. Bottom Line: Periportal THRSP-positive hepatocytes orchestrate MASH progression by recruiting CD74-positive lipid-associated macrophages through MIF signaling. Interrupting this pathway with THRSP inhibition represents a promising new strategy for treating MASH-associated liver fibrosis.

Butyrate and Butyrate-Producing Bacteria in CKM: Antioxidants | July 2026

Introduction: Cardiovascular–Kidney–Metabolic (CKM) syndrome recognizes the close interaction between obesity, type 2 diabetes, chronic kidney disease, and cardiovascular disease. This review highlights the emerging role of the gut microbiome, particularly butyrate-producing bacteria, as a central regulator of this multi-organ syndrome. Why was this review needed? Current CKM management focuses on treating individual organs rather than the underlying disease network. Growing evidence suggests that gut dysbiosis and reduced butyrate production may drive inflammation, insulin resistance, and cardiorenal dysfunction, creating new opportunities for microbiota-targeted therapy. What did the review show? Loss of butyrate-producing bacteria is consistently associated with CKM syndrome. Butyrate improves insulin sensitivity and reduces chronic metabolic inflammation. It protects against oxidative stress, endothelial dysfunction, and excessive RAAS activation. Butyrate helps maintain intestinal barrier integrity and restores gut microbial balance. Dietary fiber, direct butyrate supplementation, and microbiota-directed therapies all show potential to increase butyrate availability. The authors propose a novel gut–butyrate–CKM axis, positioning butyrate as a key mediator linking gut health with cardiovascular, renal, and metabolic function. Clinical Impact: This review shifts the focus from treating individual CKM components to targeting a common upstream mechanism. Microbiota-based interventions that restore butyrate production may become valuable adjuncts in preventing and managing CKM syndrome. Take-Home Message: Butyrate is emerging as a central molecular link between gut health and cardiovascular, kidney, and metabolic diseases. Restoring butyrate-producing bacteria through diet or microbiota-targeted therapies may represent a promising new strategy for integrated CKM management.

CK7, CK20, and CDX2 Refine Prognosis in Small Intestinal Adenocarcinoma: Annals of Oncology | 2026

Small intestinal adenocarcinoma (SIA) is a rare gastrointestinal cancer with limited disease-specific prognostic biomarkers and generally poor outcomes. This nationwide Dutch population-based study evaluated whether three routinely available immunohistochemical markers—CK7, CK20, and CDX2—have prognostic value in SIA. The analysis included 691 patients with available biomarker data and was independently validated in a separate multicenter cohort. CK20 positivity was associated with significantly better overall survival. CDX2 positivity was also associated with improved survival, consistent with findings previously reported in colorectal and gastric cancers. In contrast, CK7 positivity identified a higher-risk subgroup with more aggressive clinical features. CK7-positive tumors were more likely to be: Proximally located Advanced stage at diagnosis Microsatellite stable Loss of CK20 expression and loss of CDX2 expression were independent predictors of worse survival, even after adjustment for stage, treatment, age, sex, and tumor location. Combined CK7, CK20, and CDX2 expression profiles identified distinct prognostic categories with substantially different outcomes. Importantly, these markers are already widely available in routine pathology practice and require no additional molecular testing. The study demonstrates that immunohistochemistry can provide both diagnostic and prognostic information in SIA. The findings support incorporation of these markers into routine pathological reporting for small intestinal adenocarcinoma. Risk stratification based on CK7, CK20, and CDX2 may eventually help guide surveillance intensity, clinical trial enrollment, and treatment decision-making. Given the rarity of SIA, easily obtainable biomarkers are particularly valuable because large molecular datasets remain limited. Bottom line: CK20 and CDX2 positivity identify favorable-prognosis small intestinal adenocarcinoma, whereas CK7 positivity marks a clinically important higher-risk subgroup. Routine assessment of these inexpensive immunohistochemical markers may significantly improve prognostic stratification in this rare malignancy.

Fatty Liver Drives Hyperglycemia Through Liver–Gut Signaling : Cell Metab | Jun 2026

Introduction: Metabolic dysfunction–associated steatotic liver disease (MASLD) is closely linked to insulin resistance and type 2 diabetes, with the liver traditionally viewed as a key regulator of blood glucose through hepatic glucose production. However, emerging evidence suggests that metabolic communication between the liver and other organs may also play a critical role in glucose homeostasis. Problem Statement: While excessive hepatic gluconeogenesis is a well-established contributor to hyperglycemia, the mechanisms by which fatty liver influences distant metabolic tissues remain incompletely understood. Identifying novel liver-derived signals that disrupt glucose regulation could reveal new therapeutic targets for diabetes and metabolic liver disease. Summary: This study uncovers a previously unrecognized liver–gut communication pathway through which fatty liver promotes hyperglycemia. The investigators demonstrate that hepatocytes release alkaline phosphatase (ALP), which acts remotely on intestinal stem cells and alters their differentiation program. Mechanistically, ALP activates a signaling cascade involving α2δ-1, calcium channel translocation, and calcineurin–NFATC2 signaling, ultimately suppressing SOX21 expression. Reduced SOX21 activity lowers BMP7 production and impairs differentiation of intestinal stem cells into enteroendocrine L-cells. As a result, production of glucose-lowering gut hormones is diminished, contributing to worsening hyperglycemia. Importantly, this mechanism operates independently of increased hepatic glucose production, revealing an entirely new pathway linking fatty liver to systemic glucose dysregulation. Therapeutically, inhibition of hepatic ALP synthesis improved glycemic control and enhanced the glucose-lowering effects of metformin, suggesting potential clinical relevance. These findings redefine the role of the liver in metabolic regulation by demonstrating that fatty liver can directly influence intestinal stem cell fate and endocrine function through endocrine-like signalling. Beyond advancing understanding of MASLD-associated diabetes, the study identifies the ALP–SOX21 axis as a promising therapeutic target. Overall, this work provides compelling evidence that liver–gut communication is a fundamental regulator of blood glucose homeostasis and opens new avenues for treating metabolic disease by targeting inter-organ signalling pathways rather than hepatic metabolism alone.

Neural Remodeling Drives Early Pancreatic Carcinogenesis : Gastroenterology | Jul 2026

Introduction: Pancreatic ductal adenocarcinoma (PDAC) develops through a series of precursor lesions, beginning with acinar-to-ductal metaplasia (ADM) and progressing to pancreatic intraepithelial neoplasia and invasive cancer. While genetic alterations such as KRAS mutations are established drivers of this process, the contribution of the neural microenvironment to early pancreatic carcinogenesis remains poorly understood. Problem Statement: Neural remodeling is increasingly recognized as an important component of the pancreatic tumor microenvironment, yet the mechanisms linking nerve growth and epithelial transformation during the earliest stages of PDAC development are unclear. Understanding these interactions may reveal opportunities to intercept pancreatic cancer before invasive disease develops. Summary: This study identifies a previously unrecognized bidirectional communication network between pancreatic epithelial cells and neural elements that promotes pancreatic carcinogenesis. The investigators demonstrated that inflammation and oncogenic KRAS-driven ADM actively stimulate neurite outgrowth, while neural remodeling in turn facilitates metaplastic transformation and disease progression. Central to this interaction is ganglioside-mediated signaling, particularly involving the metabolite GM3, which serves as a key molecular mediator of neural-acinar crosstalk. Through comprehensive lipidomic, transcriptomic, and functional analyses, the authors identified β-1,4-galactosyltransferase 5 as a critical regulator of ganglioside biosynthesis that is progressively overexpressed across ADM, pancreatic intraepithelial neoplasia, and PDAC lesions in both murine and human tissues. Functional studies confirmed that this enzyme plays an essential role in initiating metaplastic changes and driving progression toward invasive pancreatic cancer. Importantly, pharmacologic inhibition of β-1,4-galactosyltransferase 5 suppressed neuronal growth, disrupted the neural-metaplastic niche, and attenuated ADM formation and progression. These findings establish neural remodeling as an active participant rather than a passive bystander in pancreatic carcinogenesis. The study provides compelling evidence that ganglioside-driven neural-epithelial interactions create a permissive microenvironment for tumor initiation and progression. By identifying glycosphingolipid metabolism and neuronal–ADM signaling as actionable targets, this work opens new avenues for early intervention strategies aimed at preventing the development of pancreatic cancer at its premalignant stages.

Engineered CAR-T Cells Boost STING Therapy in Pancreatic Cancer : Gastroenterology | Jul 2026

Introduction: Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies but has achieved limited success in solid tumors such as pancreatic cancer. Major barriers include T-cell exhaustion, poor persistence within tumors, and a profoundly immunosuppressive tumor microenvironment. Novel approaches that enhance CAR-T cell activity while simultaneously remodeling the tumor microenvironment are urgently needed. Problem Statement: STING agonists can stimulate antitumor immunity and inflame the tumor microenvironment, making them attractive partners for CAR-T therapy. However, activation of STING signaling within T cells themselves may impair CAR-T cell function, potentially limiting the effectiveness of this combination strategy. Understanding how to exploit STING activation while avoiding its detrimental effects on T cells is critical for advancing cellular therapies in pancreatic cancer. Summary: This study demonstrates a novel strategy to enhance CAR-T cell therapy in pancreatic cancer by genetically eliminating STING signaling within CAR-T cells while simultaneously administering a STING agonist. The combination resulted in superior tumor cell killing, increased CAR-T cell proliferation, reduced T-cell exhaustion, and expansion of long-lived effector-memory T cells. Mechanistic analyses revealed that the therapeutic benefit depended on preserving STING activation within cancer cells while preventing STING-mediated dysfunction in CAR-T cells. The investigators identified a positive feedback loop involving interferon-γ and tumor necrosis factor released by CAR-T cells, which enhanced tumor-cell STING signaling and further strengthened antitumor immune responses. This reciprocal interaction improved CAR-T cell fitness and amplified tumor destruction. In both xenograft and syngeneic pancreatic cancer models, STING-deficient CAR-T cells combined with the STING agonist diABZI achieved superior tumor control compared with either strategy alone. Enhanced efficacy was accompanied by increased intratumoral CAR-T cell accumulation and favorable remodeling of the tumor microenvironment. These findings provide compelling preclinical evidence that selective manipulation of STING signaling can overcome key obstacles limiting CAR-T therapy in solid tumors. The study introduces a potentially transformative strategy for pancreatic cancer and suggests that engineering CAR-T cells to resist intrinsic STING activation may unlock the full therapeutic potential of STING agonists in immune-resistant malignancies.

Adipose Tissue: Nature Reviews Endocrinology | June 2026

Adipose tissue is no longer viewed simply as a fat storage organ; it is now recognized as a highly active endocrine and neuro-regulatory organ that coordinates whole-body metabolism. Adipose tissue communicates through two major pathways: Humoral signaling (hormones, metabolites, lipid mediators, cytokines, extracellular vesicles) Neuronal signaling (sympathetic and sensory nerve networks) Adipose-derived humoral factors include: Adipokines Lipid mediators Metabolites Chemokines Exosomal microRNAs These signals regulate insulin sensitivity, glucose metabolism, lipid utilization, inflammation, vascular health, and overall cardiometabolic homeostasis. Sympathetic nerves provide rapid control of adipose tissue function, stimulating: Lipolysis in white adipose tissue Thermogenesis in brown adipose tissue Browning of white adipose tissue Sensory nerve fibers act as metabolic sensors, detecting chemical, thermal, and mechanical signals within adipose tissue and relaying information back to the central nervous system. This bidirectional communication creates a sophisticated feedback system linking adipose tissue to the brain and peripheral organs. Cold exposure activates thermogenic adipose tissue and induces release of specific adipokines and lipid mediators that improve systemic glucose and lipid metabolism. Exercise also modifies adipose signaling networks, contributing to many of the metabolic benefits traditionally attributed solely to skeletal muscle. Obesity disrupts both endocrine and neural communication within adipose tissue, resulting in: Adipokine dysregulation Chronic inflammation Insulin resistance Adipose neuropathy Similar disturbances are observed in: Type 2 diabetes Lipodystrophy Aging-related metabolic disorders Age-related deterioration of adipose signaling may contribute to declining metabolic flexibility and increased cardiometabolic risk. Emerging technologies are rapidly transforming adipose tissue research, including: Single-cell sequencing Multi-omics platforms Secretome profiling Organoid models Optogenetics Click chemistry These tools are enabling unprecedented characterization of adipose-derived signaling molecules and neural circuits. Future therapeutic opportunities may include: Synthetic adipokine analogues Lipid mediator–based therapies Neural circuit modulation Precision targeting of adipose communication pathways The review places adipose tissue at the center of modern metabolic medicine, linking obesity, diabetes, cardiovascular disease, aging, and energy homeostasis through integrated endocrine and neural networks. Bottom line: Adipose tissue functions as a sophisticated humoral–neuronal communication hub that actively regulates systemic metabolism. Understanding and manipulating these signaling networks may open new therapeutic avenues for obesity, diabetes, cardiometabolic disease, and healthy aging.

ANGPTL3 Inhibitors Deliver Broad Lipid Lowering : Eur J Prev Cardiol | June 2026

Introduction: Despite major advances in lipid-lowering therapy, many patients continue to experience residual cardiovascular risk, particularly those with elevated triglyceride-rich lipoproteins and mixed dyslipidemia. Angiopoietin-like protein 3 (ANGPTL3) has emerged as an attractive therapeutic target because of its central role in regulating lipid metabolism. Genetic studies have shown that reduced ANGPTL3 activity is associated with favorable lipid profiles and lower cardiovascular risk, prompting the development of several ANGPTL3-targeted therapies. Problem Statement: Although monoclonal antibodies, antisense oligonucleotides, and small interfering RNA therapies targeting ANGPTL3 have demonstrated promising lipid-lowering effects in individual clinical trials, the overall metabolic impact of this therapeutic class has not been comprehensively evaluated. Clarifying their efficacy across multiple lipid parameters is essential for understanding their potential role in cardiovascular risk reduction. Summary: This meta-analysis of randomized controlled trials provides a comprehensive assessment of the metabolic effects of ANGPTL3 inhibition. The analysis demonstrated that ANGPTL3-targeted therapies produce substantial reductions across a broad range of atherogenic lipoproteins, with particularly pronounced effects on triglyceride-rich lipoproteins. Significant improvements were observed in triglycerides, low-density lipoprotein cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, remnant cholesterol, and total cholesterol. Modest reductions were also noted in lipoprotein(a), an increasingly recognized cardiovascular risk factor. Importantly, ANGPTL3 inhibition achieved marked suppression of circulating ANGPTL3 levels, confirming effective target engagement. Differences among therapeutic approaches were observed, with the monoclonal antibody evinacumab demonstrating stronger reductions in several cholesterol-related parameters, while small interfering RNA agents showed particularly favorable effects on triglyceride-rich lipoproteins. Notably, no meaningful impact on systemic inflammatory markers was identified, suggesting that the benefits of ANGPTL3 inhibition are primarily mediated through lipid modification rather than anti-inflammatory mechanisms. These findings position ANGPTL3 inhibition as a promising strategy for patients with persistent dyslipidemia and residual cardiovascular risk, particularly those with elevated triglyceride-rich lipoproteins. Future outcome-driven studies will be essential to determine whether these impressive lipid improvements translate into meaningful reductions in cardiovascular events and long-term clinical benefit.

Inflammation Creates New Therapeutic Vulnerabilities in Cancer: Nature Genetics | June 2026

Cancer cells constantly adapt to inflammatory stress generated by the immune system, particularly during immune checkpoint inhibitor therapy. This study explored whether inflammatory cytokines such as interferon-γ (IFNγ), interferon-β, and TNF create new weaknesses that can be therapeutically exploited. Using genome-wide CRISPR screening across multiple cancer models, investigators identified previously unrecognized cancer dependencies that emerge specifically under inflammatory conditions. Two major targets emerged: GPI transamidase complex FITM2 (Fat Storage-Inducing Transmembrane Protein 2) These genes were not simply general survival genes; they became particularly important when tumour cells were exposed to interferon signaling. Deletion of GPI transamidase components or FITM2 significantly enhanced tumour responses to immune checkpoint blockade in preclinical models. Mechanistic studies revealed that FITM2 loss makes tumour cells highly susceptible to interferon-driven stress responses. Inflammatory cytokines triggered excessive endoplasmic reticulum stress and oxidative stress in FITM2-deficient cancer cells. This ultimately resulted in a distinctive form of programmed cell death resembling paraptosis, which differs from classical apoptosis. The findings suggest that immune activation does not only attack cancer directly but may also expose previously hidden metabolic and stress-related vulnerabilities. This represents an important conceptual advance in immuno-oncology: inflammatory signaling may create new drug targets that only become relevant during active antitumour immune responses. Combining immune checkpoint inhibitors with therapies targeting inflammation-induced dependencies could potentially improve response rates and overcome resistance. The study also highlights the growing role of functional genomics and CRISPR screening in identifying context-specific cancer vulnerabilities. Although the work remains preclinical, it provides a framework for developing combination strategies that exploit tumour adaptation to immune pressure. Future therapeutic development may focus on pharmacologic inhibition of FITM2-related pathways or GPI transamidase function alongside immunotherapy. Bottom line: Antitumour inflammatory cytokines do more than activate immune responses—they create new tumour-specific dependencies. Targeting FITM2 and GPI transamidase–related pathways may enhance the effectiveness of immune checkpoint blockade and open a new avenue for precision immuno-oncology.

F. nucleatum Linked to Worse CRC Survival : Cancer | June 2026

Introduction: The colorectal cancer (CRC) microbiome has emerged as a key factor influencing tumor development, progression, and response to treatment. Among microbial species implicated in CRC, Fusobacterium nucleatum (F. nucleatum), an oral anaerobic bacterium, has received considerable attention due to its association with tumorigenesis, immune modulation, and aggressive disease behavior. However, the relationship between intratumoral F. nucleatum and CRC-specific mortality across diverse patient populations remains incompletely understood. Problem Statement: Although previous studies have linked F. nucleatum to colorectal carcinogenesis, its impact on long-term survival and whether this association differs according to tumor location or age at diagnosis have not been clearly established. Identifying high-risk patient subgroups associated with microbial signatures could improve prognostication and guide future microbiome-targeted interventions. Summary: This study evaluated the association between intratumoral F. nucleatum and CRC-specific mortality in a large, heterogeneous United States population. The investigators found that the presence of F. nucleatum within tumor tissue was associated with significantly poorer CRC-specific survival, supporting its role as a clinically relevant prognostic biomarker. Importantly, the adverse association was not uniform across all patients. The impact of F. nucleatum was particularly pronounced in rectal cancer, where its presence was strongly linked to increased mortality, while the association was considerably weaker in colon cancers. Similarly, the relationship was substantially stronger in patients with early-onset CRC than in those diagnosed at older ages, suggesting that microbial influences may contribute differently across distinct biological subtypes of the disease. These findings reinforce the growing concept that CRC is shaped not only by tumor genetics but also by interactions with the tumor-associated microbiome. The study highlights F. nucleatum as a potential marker of aggressive disease and supports ongoing efforts to incorporate microbial profiling into CRC risk stratification. Future research should explore whether targeting F. nucleatum through microbiome-directed therapies can improve outcomes, particularly in patients with rectal cancer and early-onset CRC.

Inflammation Creates New Therapeutic Vulnerabilities in Cancer: Nature Genetics | June 2026

* Cancer cells constantly adapt to inflammatory stress generated by the immune system, particularly during immune checkpoint inhibitor therapy. * This study explored whether inflammatory cytokines such as interferon-γ (IFNγ), interferon-β, and TNF create new weaknesses that can be therapeutically exploited. * Using genome-wide CRISPR screening across multiple cancer models, investigators identified previously unrecognized cancer dependencies that emerge specifically under inflammatory conditions. * Two major targets emerged: * GPI transamidase complex * FITM2 (Fat Storage-Inducing Transmembrane Protein 2) * These genes were not simply general survival genes; they became particularly important when tumour cells were exposed to interferon signaling. * Deletion of GPI transamidase components or FITM2 significantly enhanced tumour responses to immune checkpoint blockade in preclinical models. * Mechanistic studies revealed that FITM2 loss makes tumour cells highly susceptible to interferon-driven stress responses. * Inflammatory cytokines triggered excessive endoplasmic reticulum stress and oxidative stress in FITM2-deficient cancer cells. * This ultimately resulted in a distinctive form of programmed cell death resembling paraptosis, which differs from classical apoptosis. * The findings suggest that immune activation does not only attack cancer directly but may also expose previously hidden metabolic and stress-related vulnerabilities. * This represents an important conceptual advance in immuno-oncology: inflammatory signaling may create new drug targets that only become relevant during active antitumour immune responses. * Combining immune checkpoint inhibitors with therapies targeting inflammation-induced dependencies could potentially improve response rates and overcome resistance. * The study also highlights the growing role of functional genomics and CRISPR screening in identifying context-specific cancer vulnerabilities. * Although the work remains preclinical, it provides a framework for developing combination strategies that exploit tumour adaptation to immune pressure. * Future therapeutic development may focus on pharmacologic inhibition of FITM2-related pathways or GPI transamidase function alongside immunotherapy. Bottom line: Antitumour inflammatory cytokines do more than activate immune responses—they create new tumour-specific dependencies. Targeting FITM2 and GPI transamidase–related pathways may enhance the effectiveness of immune checkpoint blockade and open a new avenue for precision immuno-oncology.

TLS Atlas: Turning Tumor Immune Architecture into a Clinical Biomarker: Science | May 2026

* Tertiary lymphoid structures are local immune hubs within tumors, but this study shows that their mere presence is not enough; their maturation, location, and cellular organization determine biological and clinical relevance. * This pan-cancer study analyzed TLS biology across 12 cancer types, combining spatial transcriptomics with artificial intelligence applied to routine H&E pathology slides. * TLSs were classified along a maturation spectrum: early TLS, primary follicle–like TLS, and secondary follicle–like TLS, reflecting increasing immune organization. * Mature TLSs showed coordinated immune architecture, including B-cell and T-cell zoning, follicular dendritic cell networks, chemokine signaling, and interferon-related immune activation. * The spatial position of TLSs mattered. Intratumoral, peritumoral, and distal TLSs were associated with different immune and tumor signaling patterns. * Tumor regions close to intratumoral TLSs showed stronger antigen presentation and immune activation signatures, including interferon and MHC class II pathways. * Tumor regions farther from TLSs showed relatively higher proliferative and invasive programs, including MYC signaling, cell-cycle activity, and epithelial–mesenchymal transition. * The authors developed an AI-based model capable of detecting and phenotyping TLSs directly from standard H&E whole-slide images, making the approach potentially scalable for routine pathology. * A maturation-aware TLS composite score performed better than simple “TLS present or absent” assessment for patient stratification across cancer and treatment settings. * This work suggests that TLS profiling may become a future immuno-oncology biomarker, helping predict prognosis, treatment response, and possibly guide trial design. * The clinical implication is important: future cancer immunotherapy decisions may depend not only on tumor genomics or PD-L1 expression, but also on the spatial immune architecture of the tumor microenvironment. * Prospective validation is still needed before TLS scoring can be used routinely in clinical practice. Bottom line: This study transforms TLSs from a descriptive pathology feature into a measurable, AI-enabled spatial biomarker with potential relevance for immunotherapy selection and cancer prognosis.

CLDN18.2 in PDAC: KRAS and Hyperglycaemia Create a Resistance Mechanism: Gut | 2026

* CLDN18.2 is emerging as a therapeutic target in gastrointestinal cancers, but its benefit in pancreatic ductal adenocarcinoma has been limited. * This study identifies a key resistance mechanism: KRAS mutation and hyperglycaemia drive O-GlcNAcylation of CLDN18.2, a sugar-based post-translational modification. * The modification occurs at the T204 site of CLDN18.2 and changes its cellular behaviour. * Instead of remaining on the tumour cell membrane where CLDN18.2-targeted therapies can bind effectively, O-GlcNAcylated CLDN18.2 accumulates in the cytoplasm. * This loss of membrane localization may explain why some pancreatic cancers expressing CLDN18.2 still respond poorly to CLDN18.2-targeted therapy. * O-GlcNAcylated CLDN18.2 is not just a passive resistance marker; it actively promotes pancreatic cancer migration, invasion, and metastasis. * Mechanistically, O-GlcNAcylated CLDN18.2 shows reduced binding to PTP1B, leading to increased tyrosine phosphorylation. * This allows CLDN18.2 to recruit Src through its SH2 domain, activating Src signaling and enhancing aggressive tumour biology. * Genetic blockade of the O-GlcNAcylation site, using the T204A mutation, restored CLDN18.2 membrane localization and reduced tumour progression in experimental models. * Pharmacological inhibition of O-GlcNAcylation produced similar benefits, suggesting that this pathway is therapeutically targetable. * Low-dose MRTX1133, a KRASG12D inhibitor, reduced CLDN18.2 O-GlcNAcylation and restored membrane localization in KRAS-mutant PDAC models. * Combining low-dose MRTX1133 with CLDN18.2-targeted therapy improved antitumour efficacy with minimal side effects in preclinical models. * The study suggests that CLDN18.2 testing should not focus only on expression level; subcellular localization may be equally important. * Hyperglycaemia may be clinically relevant because metabolic status could influence CLDN18.2 modification, localization, and therapeutic response. * This is an important translational study, but the proposed strategy still requires clinical validation before routine use. Bottom line: KRAS mutation and hyperglycaemia can convert CLDN18.2 from a membrane-accessible therapeutic target into a cytoplasmic, pro-metastatic, therapy-resistant protein. Targeting KRAS-driven O-GlcNAcylation may restore CLDN18.2-targeted therapy sensitivity in pancreatic cancer.

The Oral–X Axis: How Oral Dysbiosis Drives Systemic Disease: Genes & Diseases | June 2026

* The oral cavity contains the second largest microbial ecosystem in the human body and acts as a major interface between the external environment and multiple organ systems. * This review introduces the concept of the “Oral–X Axis,” describing the bidirectional relationship between oral microbiota and distant organs including the gut, liver, cardiovascular system, lungs, kidneys, and brain. * Oral dysbiosis is not merely a dental problem; it may contribute to the development and progression of multiple chronic systemic diseases. * Oral microbes and their metabolites can reach distant organs through bloodstream dissemination, swallowing into the gastrointestinal tract, and respiratory micro-aspiration. * Key microbial products implicated in systemic disease include lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), bile acid metabolites, and other inflammatory mediators. * These microbial signals influence immune regulation, inflammatory pathways, endothelial function, metabolic homeostasis, and tissue injury in distant organs. * The oral–gut axis is particularly important. Oral pathogens can alter intestinal microbial composition, increase gut permeability, and amplify systemic inflammation. * The oral–liver axis contributes to progression of MASLD, steatohepatitis, cirrhosis, and potentially hepatocellular carcinoma through inflammatory and metabolic mechanisms. * The oral–cardiovascular axis links periodontal disease and oral dysbiosis with atherosclerosis, endothelial dysfunction, thrombosis, and cardiovascular events. * The oral–brain axis is increasingly implicated in neuroinflammation, cognitive decline, neurodegenerative diseases, and cerebrovascular disorders. * The oral–lung axis may contribute to respiratory infections, chronic pulmonary inflammation, and adverse outcomes in chronic lung diseases. * The oral–kidney axis suggests reciprocal interactions between chronic kidney disease and oral microbial imbalance through inflammatory and metabolic pathways. * Importantly, these relationships are bidirectional. Disease in distant organs can also alter the oral microenvironment, further worsening oral dysbiosis and creating a self-perpetuating cycle. * Advances in sequencing technologies, metabolomics, and microbiome research are providing new insights into these complex host–microbe interactions. * Potential future therapeutic approaches include periodontal treatment, microbiome modulation, probiotics, targeted antimicrobial strategies, dietary interventions, and personalized microbiome-based medicine. * The review strongly argues that oral health should become an integral component of chronic disease management rather than being viewed as a separate specialty concern. Bottom line: The oral cavity functions as a systemic microbial gateway. Oral dysbiosis influences inflammation, immunity, and metabolism across multiple organs, making oral health an important but often underrecognized determinant of chronic disease outcomes.

Exercise After Bariatric Surgery: Gut Microbiota as a Metabolic Amplifier: International Journal of Obesity | June 2026

* This translational study investigated whether exercise-induced changes in gut microbiota contribute to the metabolic benefits observed after Roux-en-Y gastric bypass surgery. * Thirty-two women undergoing bariatric surgery were randomized to surgery alone or surgery plus a structured 6-month exercise program beginning three months after surgery. * Both groups achieved similar reductions in body weight, fat mass, and systemic inflammation, indicating that the additional benefits of exercise were not explained by greater weight loss. * Patients who exercised experienced superior metabolic improvements, including better HDL cholesterol levels, lower triglycerides, lower fasting glucose, and lower fasting insulin concentrations. * Exercise was associated with increased gut microbiota diversity, a feature generally linked to improved metabolic health. * The exercise group showed enrichment of bacterial genera associated with short-chain fatty acid production and favorable host metabolic regulation. * To investigate causality, researchers transplanted stool samples from post-surgery patients into high-fat diet-fed mice. * Mice receiving microbiota from exercised bariatric patients demonstrated lower fasting insulin levels and reduced insulin resistance compared with mice receiving microbiota from surgery-only patients. * These findings suggest that exercise modifies the gut microbiome in ways that contribute directly to improved insulin sensitivity. * Interestingly, glucose tolerance and systemic inflammation were similar between groups, indicating that microbiota-mediated effects may be especially important for insulin regulation rather than all metabolic outcomes. * Exercise-conditioned microbiota also partially preserved intestinal structure, suggesting potential benefits on gut integrity and host-microbe interactions. * The study strengthens the concept that exercise acts not only through muscle and energy expenditure but also through microbiome remodeling. * Clinically, the findings support exercise as an essential component of post-bariatric care, even when additional weight loss is minimal. * The study also raises the possibility that future microbiome-based therapies could mimic some of the metabolic benefits of exercise after bariatric surgery. * Limitations include a relatively small human cohort and inclusion of only female patients, requiring validation in larger and more diverse populations. Bottom line: Exercise after Roux-en-Y gastric bypass appears to reprogram the gut microbiota, generating microbial communities that improve insulin sensitivity and metabolic health beyond the effects of surgery and weight loss alone.

Bacterial Signaling Molecules Drive Colitis-Associated Cancer : Gastroenterology | Jun 2026

Introduction: Chronic inflammation is the principal driver of colitis-associated cancer (CAC) in patients with long-standing ulcerative colitis (UC). Although the intestinal microbiome has long been implicated in colorectal carcinogenesis, the precise microbial mediators linking inflammation to tumor development remain incompletely understood. Quorum-sensing molecules (QSMs), bacterial communication signals that regulate microbial behavior, have emerged as potential mediators of host–microbiome interactions, but their role in CAC has not previously been defined. Problem Statement: Current risk stratification for CAC relies largely on clinical factors such as disease duration and inflammatory burden, while mechanistic biomarkers directly linking microbial activity to carcinogenesis remain lacking. Determining whether bacterial signaling molecules actively promote tumorigenesis could reveal novel biomarkers and therapeutic targets for cancer prevention in UC. Summary: This translational study investigated the role of bacterial quorum-sensing molecules in UC-associated carcinogenesis using patient samples, murine CAC models, germ-free animals, microbiome analyses, metabolomics, and organoid systems. Investigators measured three major classes of bacterial QSMs in blood samples from patients with UC and found significantly elevated levels of short-chain N-acyl homoserine lactones (scAHLs) compared with healthy controls. Importantly, patients with active inflammation and disease duration exceeding 10 years—two major risk factors for CAC—demonstrated particularly high levels of the bacterial signaling molecule autoinducer-2. Among the identified QSMs, C6-short-chain acyl homoserine lactone (C6-scAHL) emerged as a key candidate mediator. Administration of C6-scAHL to murine models of CAC significantly increased both tumor number and tumor size, demonstrating a direct pro-tumorigenic effect. Notably, tumor promotion persisted even in germ-free mice, indicating that C6-scAHL can drive carcinogenesis independently of the broader microbiome. This finding suggests that bacterial communication molecules themselves function as biologically active mediators rather than merely markers of microbial dysbiosis. Exposure to C6-scAHL also induced microbiome and metabolomic alterations resembling those observed during chronic intestinal inflammation, further linking bacterial signaling pathways with tumor-promoting microenvironments. Mechanistic studies using murine and human colonic organoids demonstrated that C6-scAHL directly stimulated the production of proinflammatory and protumorigenic cytokines. These cytokine responses provide a plausible biological pathway through which bacterial signaling molecules enhance chronic inflammation and facilitate malignant transformation. The study therefore identifies a previously unrecognized microbiome–host communication pathway contributing to CAC development. Rather than acting through bacterial colonization alone, microbial communities may influence carcinogenesis through diffusible signaling molecules capable of modulating host immune and epithelial responses. Clinically, these findings are important because they identify circulating QSMs as potential biomarkers for CAC risk assessment. Elevated C6-scAHL and autoinducer-2 levels may help identify UC patients at greatest risk of malignant progression, particularly those with long-standing inflammatory disease. Furthermore, targeting bacterial quorum-sensing pathways represents an entirely new preventive strategy for CAC. Therapeutic interventions aimed at blocking QSM production, neutralizing signaling molecules, or interrupting downstream host responses could potentially reduce cancer risk without broadly disrupting the intestinal microbiome. Overall, this study establishes bacterial quorum-sensing molecules, particularly C6-scAHL, as active drivers of colitis-associated carcinogenesis and reveals a novel microbiome-derived signaling axis that may serve as both a biomarker and therapeutic target for cancer prevention in ulcerative colitis.

KRAS–O-GlcNAc Axis Drives CLDN18.2 Resistance in PDAC : Gut | June 2026

Introduction: Introduction: Claudin 18.2 (CLDN18.2) has emerged as an important therapeutic target in gastrointestinal malignancies, with encouraging results in gastric and gastroesophageal cancers. Its expression in pancreatic ductal adenocarcinoma (PDAC) has generated considerable interest for targeted therapies. However, clinical responses in PDAC have been less impressive than anticipated, suggesting that tumor-specific biological mechanisms may limit treatment efficacy. Problem Statement: Problem Statement: The reasons underlying the modest activity of CLDN18.2-targeted therapies in PDAC remain poorly understood. Given the near-universal prevalence of KRAS mutations and the frequent coexistence of metabolic dysfunction and hyperglycemia in pancreatic cancer, identifying mechanisms that alter CLDN18.2 localization and therapeutic accessibility is critical for improving treatment outcomes. Summary: Summary: This comprehensive translational study investigated the impact of O-linked N-acetylglucosaminylation (O-GlcNAcylation) on CLDN18.2 biology using patient samples, patient-derived organoids, patient-derived xenografts, orthotopic models, and genetically engineered mouse models. The investigators identified a previously unrecognized mechanism whereby KRAS mutations and hyperglycemia cooperate to induce O-GlcNAcylation of CLDN18.2 at the T204 residue. This post-translational modification altered CLDN18.2 subcellular trafficking, causing accumulation within the cytoplasm rather than on the cell membrane. Because CLDN18.2-targeted therapies require membrane surface expression for effective target engagement, cytoplasmic sequestration substantially reduced therapeutic susceptibility. Beyond therapeutic resistance, O-GlcNAcylated CLDN18.2 actively promoted tumor aggressiveness. Increased O-GlcNAcylation enhanced cancer cell migration, invasion, and metastatic potential, indicating that this modification is not merely a biomarker of resistance but a functional driver of disease progression. Mechanistically, O-GlcNAcylation disrupted CLDN18.2 interaction with PTP1B, resulting in enhanced tyrosine phosphorylation. This facilitated recruitment and activation of Src kinase through SH2-domain interactions, triggering downstream oncogenic signaling pathways associated with invasion and metastasis. Importantly, both genetic inhibition and pharmacologic suppression of O-GlcNAcylation restored CLDN18.2 membrane localization and attenuated tumor progression. A particularly important therapeutic finding was the effect of low-dose MRTX1133, a KRASG12D inhibitor. Treatment reduced CLDN18.2 O-GlcNAcylation, restored membrane expression, and significantly enhanced the efficacy of CLDN18.2-targeted therapy in KRAS-mutant PDAC models while maintaining a favorable toxicity profile. The study establishes a direct mechanistic link between oncogenic KRAS signaling, metabolic dysregulation, glycosylation biology, and therapeutic resistance. It also provides a biological explanation for why CLDN18.2-directed approaches have underperformed in pancreatic cancer despite target expression. From a clinical perspective, these findings have several implications. Hyperglycemia may influence responsiveness to CLDN18.2-targeted therapies, suggesting a potential role for metabolic optimization in treatment strategies. Assessment of CLDN18.2 membrane localization, rather than total expression alone, may become important when selecting patients for targeted therapy. Furthermore, combining KRAS inhibition with CLDN18.2-directed agents may represent a rational precision oncology approach for KRAS-mutant PDAC. This work is particularly significant because it converts a major resistance mechanism into a therapeutic opportunity. Rather than abandoning CLDN18.2 as a target in PDAC, the study demonstrates that modifying its cellular localization can restore drug sensitivity. Overall, the study identifies KRAS-driven O-GlcNAcylation of CLDN18.2 as a central mechanism linking tumor progression and therapeutic resistance in pancreatic cancer and provides a strong preclinical rationale for combining KRASG12D inhibition with CLDN18.2-targeted therapies to improve outcomes in this highly lethal disease.

APE1–SOX9 Axis Drives Chemoresistance in Esophageal Cancer : Gastroenterology | June 2026

Introduction: Esophageal Adenocarcinoma is an aggressive malignancy strongly associated with chronic gastroesophageal reflux disease and exposure to acidic bile reflux. Despite advances in multimodal therapy, chemotherapy resistance remains a major barrier to durable disease control and survival. Problem Statement: Resistance to platinum-based chemotherapy in esophageal adenocarcinoma is poorly understood, particularly the molecular pathways linking reflux-induced injury to tumour stemness and treatment failure. The transcription factor SOX9 has emerged as a key regulator of tumour plasticity and chemoresistance, but direct therapeutic targeting has remained difficult because of its “undruggable” nature. Summary: This translational study identified activation of the SOX9 pathway as a central driver of chemoresistance in esophageal adenocarcinoma and demonstrated that targeting the redox function of APE1 can reverse this resistant phenotype. RNA sequencing analyses revealed strong enrichment of SOX9-associated transcriptional signatures in esophageal adenocarcinoma tissues, particularly in patients with poor relapse-free survival. Using reflux-mimicking acidic bile salt exposure models, the investigators demonstrated that APE1-dependent redox signaling activates and stabilizes SOX9 protein expression. This effect persisted during oxaliplatin exposure, suggesting a direct mechanistic link between reflux biology and chemotherapy resistance. Importantly, both genetic knockdown and pharmacologic inhibition of APE1 redox activity suppressed SOX9 signaling. The study identified the APE1 redox-specific inhibitor APX2009 as a potential therapeutic strategy capable of disrupting this pathway. Mechanistically, SOX9 activation promoted expression of ALDH1A1, a stemness-associated marker linked to chemoresistance and tumour persistence. The biological findings were consistently validated across multiple advanced experimental systems, including organotypic cultures, tumour spheroids, patient-derived organoids, genetically engineered mouse models and patient-derived xenografts. Clinically relevant co-overexpression of APE1 and SOX9 was confirmed in both murine and human esophageal adenocarcinoma specimens, strengthening the translational significance of the pathway. Most importantly, combining APX2009 with oxaliplatin in patient-derived xenograft models significantly enhanced chemotherapy response and reduced SOX9 expression, supporting the therapeutic feasibility of this approach. The study is highly relevant because it provides a biologically coherent explanation for why reflux-associated esophageal adenocarcinoma develops profound resistance to systemic therapy. Rather than attempting to directly inhibit SOX9 itself, the investigators successfully targeted an upstream regulatory mechanism controlling SOX9 stability and activation. This represents an attractive therapeutic paradigm because transcription factors involved in stemness and lineage plasticity are frequently difficult to inhibit directly. The work also highlights the broader importance of redox biology in gastrointestinal carcinogenesis and treatment resistance. Clinically, these findings may ultimately support biomarker-driven therapeutic stratification using APE1/SOX9 signatures to identify patients likely to benefit from combination redox-targeted therapy. Future studies will need to validate APX2009 in larger clinical settings and determine whether APE1 inhibition can synergize with immunotherapy or radiation therapy in esophageal adenocarcinoma. Overall, this study identifies the APE1–SOX9 signaling axis as a critical mediator of reflux-driven chemoresistance in esophageal adenocarcinoma and introduces APE1 redox inhibition as a promising strategy to overcome treatment resistance and improve therapeutic response.

Single-Dose PCSK9 Base Editing Achieves Durable LDL Reduction : NEJM | May 2026

Introduction Hypercholesterolemia remains a major driver of atherosclerotic cardiovascular disease despite the availability of statins, PCSK9 inhibitors and RNA-based therapies. Lifelong treatment adherence and incomplete LDL reduction continue to limit long-term risk modification in high-risk populations. Problem Statement Whether in vivo gene editing can safely achieve durable suppression of PCSK9 and sustained LDL cholesterol reduction after a single treatment remains a major unanswered question in cardiovascular therapeutics. Summary This first-in-human phase 1 study evaluated VERVE-102, an investigational liver-directed base-editing therapy designed to permanently inactivate PCSK9 following a single intravenous infusion. VERVE-102 uses a lipid nanoparticle platform delivering messenger RNA encoding an adenine base editor together with guide RNA targeting PCSK9. The therapeutic strategy is based on naturally occurring loss-of-function PCSK9 variants associated with lifelong low LDL cholesterol levels and reduced cardiovascular risk. The study demonstrated clear dose-dependent reductions in circulating PCSK9 and LDL cholesterol levels across escalating dose cohorts. At the highest dose level, LDL cholesterol fell by more than 60%, with substantial absolute LDL reductions sustained throughout follow-up. Importantly, lipid lowering appeared durable over time, with maintained reductions extending beyond one year in available participants. These findings strongly support the feasibility of permanent in vivo gene editing as a potentially transformative “one-and-done” lipid-lowering strategy. Safety outcomes were encouraging in this early-phase trial. No dose-limiting toxicities were observed, and most adverse events consisted of mild infusion-related reactions or transient liver enzyme elevations. No major safety signal directly related to gene editing emerged during follow-up. The study represents a major milestone in clinical base-editing therapeutics. Unlike CRISPR nuclease-based approaches that create double-stranded DNA breaks, adenine base editing introduces targeted nucleotide changes without generating double-strand cleavage, theoretically reducing genomic instability risks. Clinically, the implications are substantial. Patients with familial hypercholesterolemia or premature coronary artery disease often require lifelong multidrug lipid-lowering therapy, and treatment adherence remains a persistent challenge. Durable single-dose gene editing could fundamentally alter preventive cardiology. The work also reflects the rapid convergence of lipid biology, RNA therapeutics and precision genome engineering. Following the success of siRNA therapies targeting PCSK9, permanent genomic suppression now appears technically achievable in humans. Importantly, the study focused on patients at particularly high cardiovascular risk, including those with heterozygous familial hypercholesterolemia. These populations may derive the greatest benefit from sustained LDL reduction over decades. The findings additionally raise broader questions regarding future management paradigms for chronic cardiometabolic disease. Gene editing may eventually transition cardiovascular prevention from chronic pharmacotherapy toward definitive molecular intervention. Nevertheless, several critical uncertainties remain. Long-term durability, rare off-target editing effects, immunogenicity and very late safety outcomes require extended observation before broader implementation can be considered. Cost, accessibility and ethical considerations surrounding permanent somatic gene editing will also become increasingly important as these technologies move toward larger clinical trials and potential commercialization. The study additionally reinforces the growing therapeutic relevance of hepatocyte-directed gene editing platforms, which may eventually expand beyond lipid disorders into multiple inherited and metabolic liver diseases. Overall, this phase 1 trial demonstrates that single-dose in vivo PCSK9 base editing with VERVE-102 can produce substantial, durable LDL cholesterol reduction with an encouraging early safety profile, marking a major advance toward permanent gene-editing therapies for cardiovascular disease prevention.

Pediatric Single-Cell Liver Atlas Reveals Distinct Age-Dependent Immune and Fibrotic Signatures : Hepatol Commun | May 2026

Introduction Liver development during childhood involves dynamic metabolic, immune and stromal maturation processes that differ substantially from adult liver biology. However, most hepatic single-cell reference atlases and mechanistic studies have focused predominantly on adult tissue. This gap is particularly important because pediatric liver diseases frequently display unique inflammatory, cholestatic and fibrotic phenotypes distinct from adult disorders. Problem Statement The lack of a comprehensive pediatric liver single-cell reference map limits understanding of age-specific hepatic biology and hampers accurate interpretation of cellular mechanisms underlying pediatric liver diseases such as Intestinal Failure-Associated Liver Disease. Summary This study generated a high-resolution single-cell RNA sequencing atlas of the normal pediatric liver and leveraged it to characterize disease-associated cellular programs in pediatric intestinal failure-associated liver disease. The investigators analyzed more than 42,000 cells from healthy pediatric livers and compared them with adult hepatic single-cell datasets, revealing important age-related differences in immune and stromal cell populations. One of the most striking findings was the distinct phenotype of pediatric Kupffer-like macrophages, which demonstrated heightened expression of immune activation genes including IL1B, CCL3 and CCL4 compared with adult counterparts. These findings suggest that the healthy pediatric liver exists in a more immunologically activated baseline state than adult liver tissue. Functional validation further supported this concept, with pediatric liver myeloid populations demonstrating enhanced IL-1β secretion following stimulation. The study is highly important because it challenges the assumption that adult liver reference datasets can adequately model pediatric hepatic biology. Age-dependent immune signatures appear sufficiently distinct that reliance on adult comparators alone may obscure critical disease-relevant pathways in childhood liver disorders. Using the pediatric atlas as a disease reference framework, the authors subsequently analyzed pediatric IFALD biopsies and identified fibrosis-associated transcriptional programs that would likely have been missed using adult reference tissue alone. Kupffer-like cells in IFALD showed increased expression of inflammatory and fibrosis-linked genes such as LY96, implicating innate immune activation in early pediatric fibrogenesis. Interestingly, mesenchymal populations within IFALD adopted transcriptional profiles more closely resembling adult fibrotic liver states than healthy pediatric tissue, suggesting premature activation of pro-fibrogenic remodeling programs during disease progression. The work has major translational implications for pediatric hepatology. Single-cell atlases tailored to developmental stage may become increasingly important for understanding disease heterogeneity, biomarker discovery and therapeutic targeting in pediatric liver disorders. The findings also reinforce the emerging concept that immune ontogeny strongly influences tissue-specific disease behavior. Pediatric hepatic macrophages appear functionally distinct rather than simply quantitatively different from adult populations, potentially contributing to unique inflammatory responses, fibrosis patterns and regenerative behavior in childhood liver disease. Methodologically, the study demonstrates the growing power of single-cell transcriptomics for resolving age-dependent cellular ecosystems. Beyond hepatology, developmental atlases are likely to become foundational tools across pediatric translational medicine. The atlas may additionally provide an important framework for future investigation of pediatric cholestatic disorders, metabolic liver diseases, immune-mediated hepatitis and transplant immunobiology, where developmental immune context may critically shape disease expression and therapeutic response. From a fibrosis perspective, the study also highlights how early-life inflammatory signaling may prime mesenchymal activation pathways differently than in adults. Understanding these developmental fibrogenic programs could eventually facilitate age-specific antifibrotic therapeutic approaches. Overall, this study establishes a foundational single-cell atlas of the healthy pediatric liver and demonstrates that pediatric hepatic immune and stromal biology differ substantially from adult liver tissue. The findings provide a critical developmental reference framework for mechanistic investigation of pediatric liver diseases and emphasize the importance of age-specific precision hepatology approaches.

Hereditary Pancreatitis Plasticity Accelerates KRAS-Driven Carcinogenesis : Gut | May 2026

Introduction Chronic Pancreatitis is a well-established risk factor for Pancreatic Ductal Adenocarcinoma, particularly in hereditary pancreatitis syndromes where lifetime cancer risk is markedly elevated. However, the biologic mechanisms linking chronic pancreatic inflammation to early malignant transformation remain incompletely understood. Increasing evidence suggests that inflammatory stress-induced epithelial plasticity may create a permissive environment for oncogenic KRAS-driven tumorigenesis. Problem Statement The mechanisms through which hereditary chronic pancreatitis cooperates with oncogenic KRAS Mutation during early pancreatic carcinogenesis remain poorly defined, particularly regarding epithelial cell plasticity, inflammatory signaling and stromal-immune interactions. Summary This mechanistic study combined a humanized hereditary pancreatitis mouse model carrying the pathogenic CPA1 p.N256K mutation with the established KrasG12D pancreatic cancer model to investigate how chronic inflammatory injury promotes early pancreatic neoplasia. Mice harboring both hereditary pancreatitis and oncogenic Kras mutations demonstrated striking acceleration of pancreatic remodeling, fibrosis and metaplastic lesion formation compared with Kras-mutant controls alone. The findings strongly support the concept that chronic inflammatory stress creates a biologically permissive microenvironment for KRAS-driven carcinogenesis. A major finding was the extensive epithelial plasticity induced by the CPA1 mutation across both acinar and ductal compartments. Acinar cells underwent prominent acinar-to-ductal metaplasia (ADM), an early premalignant reprogramming process increasingly recognized as a central initiating event in pancreatic cancer development. These metaplastic acinar cells demonstrated strong activation of endoplasmic reticulum stress pathways and inflammatory transcriptional programs. The study additionally identified a distinct inflammatory ductal cell phenotype termed “iDucts,” characterized by inflammatory signaling activation and altered intercellular communication. Single-cell transcriptomic analyses revealed highly dynamic multicellular interaction networks involving ductal cells, fibroblasts and granulocytes that collectively sustained pancreatic inflammation and early neoplastic progression. Importantly, the work highlights that chronic pancreatitis-associated carcinogenesis is not driven solely by epithelial mutations, but rather by coordinated interactions among stressed epithelial cells, inflammatory immune populations and activated stromal fibroblasts. These findings reinforce the concept of pancreatic cancer as a disease emerging from chronic inflammatory ecosystem remodeling rather than isolated oncogenic transformation alone. Mechanistically, CPA1 mutation-induced endoplasmic reticulum stress appears particularly important. Persistent protein misfolding stress within acinar cells likely promotes maladaptive regenerative responses, inflammatory cytokine release and dedifferentiation toward duct-like phenotypes vulnerable to KRAS-mediated transformation. The study is also notable because it models hereditary chronic pancreatitis using a clinically relevant humanized mutation rather than experimentally induced acute injury models. This provides a more biologically faithful framework for understanding the exceptionally high pancreatic cancer risk observed in hereditary pancreatitis patients. Clinically, the findings support intensified surveillance strategies in hereditary pancreatitis populations and further emphasize the importance of targeting inflammatory and stromal signaling pathways during early pancreatic carcinogenesis. The identified inflammatory ductal phenotypes and cell-cell communication networks may additionally represent future therapeutic or biomarker targets for pancreatic cancer interception. Overall, this translational study demonstrates that hereditary pancreatitis-associated epithelial plasticity, inflammatory remodeling and multicellular signaling networks cooperate with oncogenic KRAS to accelerate early pancreatic carcinogenesis. The work provides important mechanistic insight into how chronic pancreatic injury drives malignant transformation and advances understanding of inflammation-associated pancreatic cancer initiation.

Autophagic HIF-1α Degradation Extends Mammalian Lifespan : Nat Aging | May 2026

Introduction Hypoxia-Inducible Factor 1-alpha is a master regulator of cellular adaptation to hypoxia, coordinating metabolic reprogramming, angiogenesis and stress responses. Although transient HIF-1α activation is protective during acute hypoxic stress, chronic HIF-1α accumulation has increasingly been linked to inflammation, mitochondrial dysfunction, senescence and age-related tissue injury. This landmark study explored why certain tissues age more slowly than others and identified a previously unrecognized autophagy-mediated mechanism regulating hypoxia-associated aging. Problem Statement The molecular mechanisms underlying differential organ aging rates remain poorly understood. In particular, how chronically hypoxic tissues avoid long-term HIF-1α–mediated cellular stress and whether these protective pathways can be therapeutically transferred to other organs has remained unclear. Summary Using cross-tissue molecular aging analyses, investigators identified the intervertebral disc (IVD) as an unusually slow-aging tissue despite its chronically hypoxic microenvironment. Mechanistic studies revealed that nucleus pulposus cells within the IVD possess a unique ability to selectively degrade HIF-1α through optineurin-mediated autophagy, thereby uncoupling persistent hypoxia from sustained HIF-1α accumulation. This selective autophagic degradation pathway prevented chronic cellular stress signaling, reduced senescence-associated injury and preserved tissue homeostasis despite prolonged hypoxic exposure. The findings challenge the traditional assumption that hypoxia necessarily results in persistent HIF-1α stabilization and instead demonstrate that regulated HIF-1α turnover may be critical for healthy aging under hypoxic conditions. Building upon this biologic mechanism, investigators developed a novel small-molecule autophagy-targeting compound termed HATC designed to promote selective autophagic degradation of HIF-1α across tissues. Systemic administration of HATC in aged mice substantially reduced HIF-1α accumulation in multiple organs and produced broad geroprotective effects. Remarkably, weekly HATC treatment ameliorated numerous age-related pathologies while significantly extending both median and maximum lifespan. Median lifespan increased by approximately 14%, while maximal lifespan improved by roughly 12%. Treated animals additionally demonstrated improvements across multiple physiologic aging phenotypes, suggesting enhancement of overall healthspan rather than isolated survival prolongation. Mechanistically, the study positions chronic HIF-1α accumulation as a potentially central driver of mammalian aging biology. Persistent HIF-1α signaling may promote metabolic dysfunction, inflammatory activation and cellular stress responses that progressively impair tissue integrity with age. Selective autophagic degradation therefore represents a targeted strategy for restoring cellular homeostasis without globally suppressing adaptive hypoxia signaling. The work is particularly important because it introduces a new therapeutic paradigm within geroscience: selective degradation of aging-associated signaling proteins through engineered autophagy tethering rather than conventional enzymatic inhibition. This strategy may allow highly specific modulation of pathogenic pathways while minimizing broader physiologic disruption. Overall, this groundbreaking study identifies optineurin-mediated autophagic degradation of HIF-1α as a key endogenous longevity mechanism in slowly aging tissues and demonstrates that pharmacologic transfer of this pathway can extend mammalian lifespan. The findings establish HIF-1α-directed autophagy modulation as a highly promising emerging strategy in translational aging biology and geroprotective therapeutics.

Microvillar Contacts Govern PD-1 Checkpoint Signaling : Sci Immunol | May 2026

Introduction Programmed Cell Death Protein 1 blockade has revolutionized cancer immunotherapy, yet the precise spatial and temporal mechanisms by which PD-1 suppresses T-cell activation remain incompletely understood. Although PD-1 signaling is known to inhibit T-cell receptor (TCR) activation through recruitment of phosphatases such as SHP2, how checkpoint signaling is physically organized at the immune synapse has remained unclear. This mechanistic study identifies nanoscale microvillar contacts as critical hubs for early PD-1–mediated immune regulation. Problem Statement The cellular architecture governing integration of PD-1 inhibitory signaling with TCR activation has not been fully resolved. Furthermore, current checkpoint-blocking antibodies may paradoxically induce inhibitory signaling under certain conditions, potentially limiting therapeutic efficacy. Summary Using advanced fluorescence imaging and nanoscale spatial analyses, investigators demonstrated that PD-1 signaling is initiated within dynamic microvillar close contacts formed during T-cell interaction with target cells. These specialized nanoscale membrane protrusions function as highly organized signaling hubs where PD-1 and TCR pathways are integrated during the earliest phases of immune synapse formation. PD-1 signaling began immediately as microvillar contacts formed and selectively shortened the duration of TCR signaling without substantially altering signal amplitude. Mechanistically, PD-1 directly recruited SHP2 to microvillar contacts, thereby suppressing proximal TCR activation. In parallel, PD-1 indirectly reduced T-cell activation by limiting cell spreading, decreasing formation of additional close contacts and reducing overall TCR engagement efficiency. Importantly, the inhibitory effects of PD-1 were particularly pronounced in settings of low-affinity or low-density antigen presentation, suggesting that checkpoint signaling preferentially suppresses weaker antitumor immune responses. These findings provide mechanistic insight into why poorly immunogenic tumors may be especially vulnerable to PD-1–mediated immune escape. One of the most clinically significant observations involved the behavior of the PD-1 blocking antibody Nivolumab. Surprisingly, investigators found that Fc receptor–mediated trapping of nivolumab-bound PD-1 within microvillar contacts paradoxically induced inhibitory signaling rather than fully blocking checkpoint activity. This unintended agonistic effect promoted persistent SHP2 recruitment and residual immune suppression despite therapeutic antibody binding. The authors subsequently engineered modified antibodies designed to prevent PD-1 trapping at microvillar contacts. These engineered variants eliminated agonistic signaling effects and demonstrated improved checkpoint blockade efficacy, highlighting an important new principle in immunotherapy antibody design. The findings suggest that spatial organization and membrane dynamics may critically influence checkpoint inhibitor performance beyond simple receptor occupancy. Conceptually, the study reframes immune checkpoint signaling as a highly localized nanoscale process occurring within transient microvillar structures rather than diffuse immune synapses. This model provides a new mechanistic framework explaining how inhibitory and activating immune signals are integrated with extraordinary spatial precision during T-cell target recognition. Overall, this landmark study identifies microvillar close contacts as central regulators of PD-1 checkpoint biology and reveals that antibody-mediated PD-1 trapping may inadvertently preserve inhibitory signaling. These findings may guide development of next-generation immune checkpoint inhibitors with improved spatial dynamics, enhanced antitumor activity and reduced functional resistance.

Autophagy Modulation in Cancer: Therapeutic Promise and Complexity : Nat Rev Drug Discov | May 2026

Introduction Autophagy is a highly conserved cellular homeostatic mechanism that enables recycling of intracellular components, removal of damaged organelles and adaptation to metabolic stress. In cancer biology, autophagy has emerged as a paradoxical process with context-dependent tumor-suppressive and tumor-promoting roles. Increasingly, modulation of autophagy is being explored as a therapeutic strategy across multiple stages of oncogenesis and anticancer treatment. Problem Statement Despite intense therapeutic interest, targeting autophagy in cancer remains highly challenging because autophagy exerts divergent effects depending on tumor type, disease stage, immune context and treatment setting. Furthermore, currently available pharmacologic autophagy inhibitors lack specificity and may adversely affect normal tissues and antitumor immune responses. Summary This comprehensive review outlines the multifaceted role of autophagy across cancer initiation, progression, immune regulation and therapeutic resistance. In early carcinogenesis, defective autophagy promotes genomic instability, oxidative stress, chronic inflammation and accumulation of damaged cellular components, thereby facilitating malignant transformation. These observations support the tumor-suppressive role of basal autophagy during early oncogenesis. Conversely, once tumors are established, proficient autophagic activity often becomes advantageous for malignant cells. Tumor cells exploit autophagy to survive hypoxia, nutrient deprivation, oxidative stress and therapeutic pressure within hostile tumor microenvironments. Autophagy additionally supports mitochondrial fitness, metabolic plasticity and adaptation to cytotoxic therapies, thereby contributing to tumor persistence and treatment resistance. The review highlights growing evidence that autophagy strongly influences anticancer immunity. Depending on context, autophagy may either enhance or impair immune-mediated tumor elimination. In some settings, autophagy facilitates antigen presentation, immunogenic cell death and T-cell activation, thereby supporting immunosurveillance. Conversely, autophagic pathways may also protect tumor cells from immune-mediated cytotoxicity and contribute to resistance against immune checkpoint blockade. Importantly, the authors emphasize that healthy immune cells themselves depend heavily on autophagy for maturation, survival and effector function. Cytotoxic T lymphocytes, dendritic cells and other immune effectors require intact autophagic machinery to sustain antitumor responses. This creates major therapeutic complexity because indiscriminate systemic autophagy inhibition could simultaneously impair both tumor survival and immune-mediated tumor control. The review further discusses current pharmacologic strategies targeting autophagy, including lysosomal inhibitors such as hydroxychloroquine, upstream kinase modulators and novel selective autophagy-targeting agents. However, most clinically available inhibitors remain relatively nonspecific and incompletely suppress autophagic flux. Variable pharmacodynamic activity, compensatory resistance pathways and systemic toxicity have limited clinical success thus far. A major conceptual advance emphasized throughout the review is that autophagy should no longer be viewed as a binary therapeutic target. Instead, future approaches will likely require precision modulation tailored to tumor genotype, metabolic state, immune microenvironment and treatment timing. Context-specific strategies integrating autophagy modulation with chemotherapy, radiotherapy, targeted therapy or immunotherapy may ultimately prove most effective. Overall, this state-of-the-art review positions autophagy as one of the most biologically complex therapeutic vulnerabilities in oncology. The authors underscore that successful clinical translation will require highly selective, context-aware approaches capable of exploiting tumor-specific autophagic dependencies while preserving protective homeostatic and immune functions in normal tissues.

Hepatocyte CCL9 Drives Fibrogenic Immune Signaling : Hepatology | Apr 2026

Introduction Liver Fibrosis results from persistent hepatic injury, chronic inflammation and activation of hepatic stellate cells (HSCs). Chemokine-mediated immune recruitment is central to fibrogenesis, yet many inflammatory pathways governing hepatocyte–immune–stromal interactions remain incompletely characterized. This mechanistic study investigated the role of hepatocyte-derived Ccl9, the murine homolog of human CCL15, in regulating hepatic inflammation and fibrosis progression. Problem Statement Although inflammatory chemokines are known contributors to liver injury, the specific role of hepatocyte-derived Ccl9 in coordinating immune cell recruitment, macrophage polarization and direct stellate cell activation during fibrosis has remained unclear. Summary Using multiple murine fibrosis models including carbon tetrachloride exposure, bile duct ligation and diet-induced steatohepatitis, investigators demonstrated marked upregulation of Ccl9 expression within fibrotic livers. Injured hepatocytes represented the primary cellular source of Ccl9, while the transcription factor Myc was identified as a major upstream regulator driving its induction during hepatic injury. Functional studies using hepatocyte-specific Ccl9 knockout mice showed substantial attenuation of fibrosis and liver injury across all experimental models. Ccl9 deletion reduced inflammatory infiltration, hepatic macrophage accumulation and neutrophil recruitment, supporting a central role for hepatocyte-derived chemokine signaling in orchestrating fibrogenic inflammation. Similar antifibrotic effects were achieved using Ccl9-neutralizing antibodies, highlighting potential translational therapeutic relevance. Mechanistically, Ccl9 promoted recruitment and activation of inflammatory macrophages through the Ccr1 receptor pathway. Importantly, Ccl9 shifted macrophage polarization toward a proinflammatory M1 phenotype and amplified inflammatory cytokine signaling within injured liver tissue. Beyond immune modulation, the study demonstrated that Ccl9 directly activated hepatic stellate cells through a distinct intracellular signaling cascade. Specifically, Ccl9–Ccr1 signaling recruited Myh9 and enhanced Wnt pathway activation via Myh9-mediated ubiquitination of Gsk3β, thereby promoting stellate cell activation and extracellular matrix production. This dual role — simultaneously amplifying inflammatory immune signaling and directly stimulating fibrogenic stellate pathways — positions Ccl9 as a particularly important upstream mediator of fibrosis progression. The findings are especially notable because they identify hepatocytes not merely as passive injury targets but as active immunoregulatory drivers of fibrogenesis through chemokine secretion. The study also strengthens the growing concept that fibrosis progression depends on tightly integrated hepatocyte–immune–mesenchymal signaling networks rather than isolated stellate cell activation alone. Overall, this translational work identifies the hepatocyte-derived Ccl9/Ccr1 axis as a major promoter of liver fibrosis progression through coordinated immune recruitment, macrophage polarization and direct HSC activation. The data support therapeutic targeting of Ccl9 signaling as a potentially promising antifibrotic strategy across diverse chronic liver diseases.

B-Cell Dysfunction and TLS Biology in iCCA : Gut | May 2026

B-Cell Dysfunction and TLS Biology in iCCA : Gut | May 2026 Introduction Intrahepatic Cholangiocarcinoma is characterised by a highly desmoplastic and immunosuppressive tumour microenvironment (TME), contributing to poor responsiveness to systemic therapies and immune checkpoint inhibitors. While T-cell biology in iCCA has been extensively investigated, the role of tumour-infiltrating B lymphocytes and tertiary lymphoid structures (TLS) remains poorly defined. This study comprehensively dissected the phenotypic, transcriptional and functional characteristics of B cells within iCCA and evaluated their relationship with chemoimmunotherapy response. Problem Statement The immunological contribution of B cells in iCCA is incompletely understood. Whether B cells exert antitumour immunity, become functionally suppressed by the TME, or predict response to immunotherapy remains unclear. Identification of B-cell–mediated immune pathways could open new avenues for biomarker development and therapeutic modulation. Summary Using multimodal single-cell technologies, high-dimensional flow cytometry, transcriptomics, imaging mass cytometry and ex vivo coculture systems, the investigators demonstrated that iCCA harbours a profoundly dysfunctional B-cell compartment. B cells were enriched predominantly in peritumoural regions rather than within tumour cores, where they frequently organised into mature tertiary lymphoid structures associated with improved disease-free survival. In contrast, intratumoural B cells were sparse, immature and functionally suppressed. Single-cell RNA sequencing identified multiple B-cell subpopulations with marked suppression of B-cell receptor signalling, differentiation pathways, inflammatory programs and humoral immune responses within tumours. Tumour-infiltrating B cells demonstrated downregulation of activation-associated genes including CD79B, MYC, CD69 and FOS, alongside increased stress-response signatures. Flow cytometry further confirmed depletion of memory B cells, plasmablasts and activated B-cell subsets within tumours, with enrichment of dysfunctional double-negative and immature phenotypes. Functionally, patients with iCCA displayed impaired systemic humoral immunity, including reduced circulating IgM, IgA, IgE and later-stage class-switched immunoglobulin subclasses, suggesting defective B-cell maturation and class-switch recombination. Tumour-associated B cells expressed increased immunosuppressive cytokines including IL-10 and TGF-β while exhibiting reduced effector cytokines such as IL-6 and IL-12. Mechanistically, extensive ligand–receptor interactome analyses revealed that both tumour cells and cancer-associated fibroblasts actively induce B-cell dysfunction through IL-6 and TGF-β–dependent signalling pathways. Ex vivo coculture experiments confirmed that iCCA cells and fibroblasts suppress B-cell maturation, reduce BAFFR expression and promote expansion of exhausted and atypical B-cell subsets. Importantly, combined blockade of IL-6R and TGF-β signalling restored B-cell activation, differentiation and memory/plasmablast generation, highlighting a therapeutically targetable immune axis. The study additionally demonstrated important predictive implications during chemoimmunotherapy with durvalumab, gemcitabine and cisplatin. Responders exhibited higher frequencies of circulating BAFFR-positive B cells, increased BAFF levels and emergence of hyperexpanded B-cell clonotypes. Elevated BAFFR expression correlated with improved progression-free and overall survival, suggesting that B-cell activation status may function as a clinically relevant predictive biomarker for immunotherapy responsiveness in iCCA. Overall, this landmark translational study establishes that iCCA is characterised by profound B-cell immunosuppression orchestrated by tumour-stromal interactions. The findings position B cells, BAFFR signalling and TLS maturation as potential biomarkers and therapeutic targets, supporting future strategies aimed at restoring B-cell function and enhancing chemoimmunotherapy efficacy in biliary tract cancers.

Gut-Derived Ammonia Drives CD8 T-Cell–Mediated MASH : J Clin Invest | May 2026

Introduction Metabolic Dysfunction-Associated Steatohepatitis is increasingly recognized as a multisystem disorder involving complex interactions between metabolism, intestinal microbiota, immune activation and fibrosis. Although gut dysbiosis has long been implicated in MASH progression, the precise microbial metabolites and immune pathways driving hepatic injury remain incompletely defined. This translational study investigated how ammonia-producing intestinal bacteria modulate hepatic immune injury and evaluated the therapeutic potential of the glycine-based tripeptide DT-109. Problem Statement The mechanisms linking intestinal microbial dysbiosis to hepatic immune-mediated injury in MASH remain poorly understood. In particular, whether gut-derived ammonia directly contributes to hepatic inflammation and cytotoxic immune activation beyond its established role in cirrhosis-associated encephalopathy has remained unclear. Summary Using integrated human, murine and non-human primate MASH models, this study identified a major expansion of the ammonia-producing bacterium Clostridium perfringens within the intestinal microbiome during MASH progression. Elevated intestinal ammonia levels were associated with impaired intestinal barrier integrity, increased systemic exposure to microbial products and heightened hepatic immune activation. Mechanistically, gut-derived ammonia promoted FosB-dependent upregulation of chemokine CCL5 within hepatic CD8+ T cells, driving enhanced cytotoxic T-cell activity and liver injury. Functional experiments using microbiota transplantation and genetically modified ammonia-deficient C. perfringens mutants confirmed a causal relationship between bacterial ammonia production and MASH severity. The study therefore establishes ammonia not merely as a metabolic waste product but as an active immunomodulatory mediator within the gut–liver axis. Therapeutically, DT-109 demonstrated significant efficacy across both murine and non-human primate models. Treatment reduced intestinal C. perfringens abundance, lowered ammonia production, restored intestinal barrier function and attenuated hepatic CD8+ T-cell dysregulation. These improvements translated into reduced steatohepatitis severity and amelioration of inflammatory liver injury. The findings suggest that modulation of microbial ammonia metabolism may represent a novel therapeutic strategy for MASH distinct from traditional metabolic-targeted approaches. Overall, this study identifies a previously unrecognized microbiota–ammonia–CD8 T-cell axis contributing to MASH pathogenesis and positions DT-109 as a promising microbiome-directed immunometabolic therapy. The work further reinforces the emerging concept that intestinal microbial metabolites actively shape hepatic immune injury and may provide tractable therapeutic targets in progressive steatotic liver disease.

circPLCE1 Loss Drives Fibrosis in Crohn’s Disease : Gut | May 2026

Introduction Intestinal fibrosis is a major complication of Crohn’s Disease and remains a leading cause of bowel strictures, obstruction and repeated surgery. Current anti-inflammatory therapies have limited efficacy once fibrotic remodeling becomes established, highlighting the urgent need for mechanistic antifibrotic targets. Emerging evidence suggests that fibroblast metabolic reprogramming is central to organ fibrosis, although its contribution to intestinal fibrogenesis in Crohn’s disease has remained incompletely understood. Problem Statement The metabolic pathways that sustain activated intestinal fibroblasts and extracellular matrix deposition in Crohn’s disease are poorly characterized. In particular, the role of the Pentose phosphate pathway and its upstream regulatory networks in intestinal fibrosis has not previously been defined. Summary Using integrated metabolomics, single-cell RNA sequencing and spatial transcriptomics from paired strictured and non-strictured intestinal tissue, this study identified marked activation of the pentose phosphate pathway (PPP) within intestinal fibroblasts during Crohn’s-associated fibrosis. The investigators demonstrated that xylulokinase (XYLB)-mediated generation of xylulose-5-phosphate promoted extracellular matrix synthesis through epigenetic enhancement of collagen transcription. This established PPP activation as a direct driver of fibroblast profibrotic activity rather than merely a metabolic bystander phenomenon. Mechanistically, the study identified downregulation of the circular RNA circPLCE1 as a central upstream regulator of this metabolic reprogramming. Reduced circPLCE1 expression enhanced PPP activation, increased glycolytic flux and elevated nicotinamide adenine dinucleotide phosphate production, collectively promoting fibroblast activation and intestinal fibrosis both in vitro and in murine fibrosis models. Importantly, circPLCE1 directly interacted with the catalytic domain of XYLB, competitively inhibiting its enzymatic activity. Loss of circPLCE1 therefore restored XYLB function and led to accumulation of xylulose-5-phosphate, driving sustained fibrogenic signaling. Fibroblast-specific circPLCE1 knockdown in vivo significantly aggravated intestinal fibrosis, confirming the biological importance of this regulatory axis. The study further linked metabolic rewiring to epigenetic collagen regulation, reinforcing the emerging concept that immunometabolic pathways are central to chronic fibrostenotic disease progression in Crohn’s disease. Overall, these findings identify a novel circPLCE1–XYLB–Xu5P metabolic axis governing intestinal fibrogenesis and position fibroblast PPP modulation as a promising antifibrotic therapeutic strategy in Crohn’s disease. The work also expands understanding of how non-coding RNAs regulate stromal cell metabolism and tissue remodeling in chronic intestinal inflammation.

Neonatal Metabolomic Signatures Predict Future IBD : Gastroenterology | May 2026

Introduction Early-life environmental and immunologic exposures are increasingly implicated in the pathogenesis of Inflammatory bowel disease. Altered neonatal microbiota, elevated fecal calprotectin and immune dysregulation have previously been observed in children born to mothers with IBD, suggesting that disease susceptibility may begin very early in life. However, whether metabolic abnormalities are already detectable at birth in individuals who later develop Crohn’s disease or ulcerative colitis has remained unclear. Problem Statement Although metabolomic disturbances have been identified in established and preclinical IBD, studies investigating neonatal metabolic signatures preceding future disease onset are extremely limited. Determining whether altered metabolites are present immediately after birth could provide important mechanistic insight into early disease programming and identify novel biomarkers of future IBD susceptibility. Summary Using neonatal dried blood spots from the Danish National Biobank, this population-based cohort study performed untargeted metabolomics in 520 individuals who later developed IBD and 520 matched controls. Overall global metabolomic composition did not differ significantly between future IBD cases and controls. However, focused feature-selection analysis identified 21 metabolites associated with later Crohn’s disease and four metabolites associated with future ulcerative colitis. Notably, distinct metabolite signatures were observed for pediatric-onset and adult-onset disease, with no overlap between age-at-onset groups, suggesting divergent developmental trajectories of IBD susceptibility from birth onward. The altered metabolites included amino acid derivatives, peptides, nucleotides/nucleosides and acyl-carnitines, implicating pathways related to protein turnover, mitochondrial metabolism and immune activation. Among the most biologically compelling findings was pseudouridine, which was strongly associated with future Crohn’s disease. Pseudouridine reflects increased transfer RNA turnover and has previously been linked to inflammatory signaling. The study demonstrated correlations between pseudouridine and inflammatory cytokines including TNF-α, IL-6 and IL-4, suggesting that neonatal immune activation may precede overt intestinal disease by many years. Genetic association analyses further linked several metabolites to loci involved in amino acid metabolism and mitochondrial transport pathways. Importantly, no metabolites overlapped between Crohn’s disease and ulcerative colitis, reinforcing the concept that these conditions may have distinct early-life metabolic origins. The findings also differed from previous Canadian neonatal metabolomics studies, likely because of the broader untargeted metabolomic platform and use of dried blood spot specimens rather than serum. Although the study was exploratory and limited by incomplete metabolite annotation and lack of external validation, it provides important proof-of-concept evidence that metabolic perturbations associated with future IBD may already be present within days of birth. These results support the hypothesis that early developmental immune-metabolic programming contributes to later IBD susceptibility and establish a foundation for future mechanistic and predictive biomarker studies.

CTNNA1-Associated HDGC Spectrum : Gut | May 2026

Introduction Germline CTNNA1 variants have emerged as an important cause of hereditary diffuse gastric cancer (HDGC), yet their clinical penetrance, disease spectrum and biological mechanisms have remained poorly defined. Unlike the classical HDGC gene CDH1, uncertainty surrounding CTNNA1-associated cancer risk has limited the development of evidence-based surveillance and prophylactic strategies. This large international study integrated molecular, functional and clinical data from 351 carrier families and more than 37,000 controls to clarify genotype–phenotype associations and refine clinical testing criteria. Problem Statement The study demonstrated that truncating CTNNA1 variants are the clinically relevant oncogenic alterations driving HDGC predisposition. CTNNA1 truncating transcripts underwent nonsense-mediated decay, resulting in loss of αE-catenin expression in diffuse gastric cancers. Carriers of truncating variants had an eightfold higher likelihood of diffuse gastric cancer compared with non-truncating carriers, while lobular breast cancer also recurred within affected families. Importantly, CTNNA1 behaved as a moderate-penetrance HDGC gene, with substantially lower gastric and breast cancer risk than CDH1. In contrast, non-truncating variants clustered within the αE-catenin middle fragment domain and were strongly associated with macular dystrophy patterned-2 rather than cancer predisposition. Summary This study substantially redefines the CTNNA1-associated HDGC spectrum and provides the strongest evidence to date supporting truncating CTNNA1 variants as pathogenic drivers of diffuse gastric cancer susceptibility. The authors propose simplified “Porto” testing criteria that improve identification of clinically relevant CTNNA1 carrier families while maintaining diagnostic specificity. The findings support individualized surveillance and prophylactic strategies distinct from those used in CDH1-associated HDGC, recognizing CTNNA1 as a moderate-risk gastric cancer predisposition gene rather than a highly penetrant syndrome. These data also establish a mechanistic framework for future CTNNA1 variant classification and precision hereditary gastric cancer management.

Parasutterella-Driven NETosis Worsens UC and CAC : Gut | May 2026

Introduction Microbial dysbiosis plays a pivotal role in the pathogenesis of ulcerative colitis (UC) and inflammation-associated colorectal cancer. Among emerging pathobionts, Parasutterella excrementihominis has recently gained attention because of its enrichment in patients with UC, although its direct mechanistic contribution to intestinal inflammation and tumorigenesis has remained uncertain. Problem Statement The pathways through which specific gut bacteria promote chronic mucosal inflammation and colitis-associated colorectal cancer (CAC) are incompletely understood. In particular, the role of bacterial metabolites in triggering pathogenic neutrophil extracellular trap formation (NETosis) and inflammation-driven carcinogenesis has not been clearly defined. Summary This study identified P. excrementihominis as a potent microbial driver of experimental colitis and CAC progression. Stool analyses confirmed significant enrichment of the bacterium in patients with UC. In murine dextran sulphate sodium colitis and azoxymethane/DSS CAC models, colonisation with P. excrementihominis markedly aggravated intestinal inflammation, enhanced tumour burden and promoted colonic neutrophil infiltration with excessive NET formation. Mechanistic investigations demonstrated that the bacterium altered host carbohydrate metabolism, resulting in increased production of succinic acid and 6-hydroxyhexanoic acid. These metabolites triggered pathogenic NETosis through activation of succinate receptor-1 and GPR84 signalling pathways in lipopolysaccharide-primed neutrophils. Importantly, this process was dependent on Gasdermin D-mediated NETosis, linking microbial metabolic activity directly to inflammatory tissue injury and tumorigenesis. Neutrophil-specific deletion of gasdermin D significantly attenuated metabolite-induced tumour progression, confirming the central pathogenic role of NETosis. The study provides compelling evidence that microbial metabolites can orchestrate immune-mediated colorectal carcinogenesis through neutrophil activation pathways. These findings position P. excrementihominis and its metabolite–NETosis axis as promising therapeutic targets for UC and CAC, with potential implications for microbiome-directed interventions in inflammation-driven colorectal cancer.

Loneliness, Cortisol and NK Dysfunction in Chronic Stress : Psychoneuroendocrinology | May 2026

Introduction Psychosocial stressors such as loneliness, chronic stress and social disadvantage are increasingly recognized as major contributors to cardiometabolic disease. Natural killer cell activity plays a central role in immune surveillance, inflammation regulation and cardiovascular health, yet the biological pathways linking chronic stress to NK-cell dysfunction remain incompletely understood. Problem Statement Although cortisol is a key neuroendocrine mediator of chronic stress through activation of the hypothalamic–pituitary–adrenal axis, its relationship with NK-cell dysfunction in humans—particularly in populations exposed to persistent psychosocial adversity—has not been clearly established. The interaction between loneliness, cortisol signalling and innate immune suppression remains poorly characterized. Summary This translational study explored the relationship between psychosocial stress, cortisol and NK-cell biology in African American women from under-resourced communities who were at elevated cardiovascular risk. Higher plasma cortisol levels were associated with reduced proportions of proliferative NK-cell subsets, and this relationship was strongly modified by loneliness, suggesting that social isolation amplifies cortisol-mediated immune dysregulation. Individuals with moderate-to-high loneliness demonstrated significant inverse associations between cortisol and NK-cell distribution, whereas this pattern was absent in participants with low loneliness scores. Functional analyses further demonstrated that elevated cortisol correlated with impaired NK-cell degranulation and reduced interferon-γ production, indicating compromised cytotoxic immune activity. Mechanistic experiments showed that cortisol directly suppressed NK-cell function in vitro, reducing degranulation and cytokine production while increasing PD-1 surface expression. Importantly, the study identified FABP4 as a potential mediator of this dysfunction, as inhibition of FABP4 restored PD-1 expression and NK-cell cytolytic activity. Transcriptomic profiling further supported suppression of NK-cell cytotoxic pathways in individuals with high cortisol levels. These findings provide important mechanistic insight into how chronic psychosocial stress and loneliness may impair innate immunity and potentially contribute to heightened cardiovascular and cancer risk. The study also highlights potential therapeutic relevance of targeting PD-1 and FABP4 pathways to reverse stress-associated immune dysfunction. Overall, the work establishes loneliness as a biologically relevant modifier of cortisol-driven NK-cell impairment and reinforces the growing concept that adverse social determinants of health exert direct immunometabolic effects.

Human Di-lineage Hepatic Spheroids Reproduce Key Features of MASLD : Cell Mol Gastroenterol Hepatol | May 2026

Introduction Metabolic dysfunction-associated steatotic liver disease affects nearly one-third of the global population and spans a disease spectrum from steatosis to steatohepatitis, fibrosis and cirrhosis. Despite major advances in clinical hepatology, the molecular mechanisms driving transition from simple steatosis to progressive fibrotic liver injury remain incompletely understood. Problem Statement Existing in vitro liver disease models—including immortalized hepatocyte systems and induced pluripotent stem cell organoids—often fail to fully reproduce the complex metabolic and fibrotic interactions observed in human MASLD. More physiologically relevant human models are needed to better study disease biology and evaluate antifibrotic therapies. Summary This translational study developed a human di-lineage hepatic spheroid platform combining primary human hepatocytes and hepatic stellate cells in physiologic proportions to model steatotic liver disease and fibrosis. Exposure to free fatty acids and transforming growth factor-β1 successfully induced hallmark features of MASLD and MASH, including intracellular lipid accumulation, increased collagen deposition, impaired ApoB100 secretion and development of a profibrotic secretory profile characterized by reduced matrix metalloproteinases and increased tissue inhibitors of metalloproteinases. Multiomic integration using transcriptomics and proteomics demonstrated strong concordance between gene and protein expression and identified activation of extracellular matrix remodeling and TGFB signaling alongside suppression of metabolic and cholesterol pathways. Importantly, the molecular signatures observed in the spheroids closely mirrored fibrosis-associated gene expression patterns in human liver tissue from the GepLiver database, supporting translational relevance of the model. Key fibrosis-associated markers such as COL1A1, ACTA2, TGFBI and PLOD2 were strongly upregulated, whereas lipid metabolic regulators including APOA2 and FABP1 were suppressed, reflecting simultaneous fibrotic remodeling and metabolic dysfunction. The spheroids also demonstrated pharmacologic responsiveness to resmetirom and obeticholic acid, both of which reduced lipid accumulation and collagen expression, paralleling observations from clinical studies. Although limited by exclusion of additional liver-resident immune and endothelial cell populations, this simplified human primary-cell platform provides a robust and physiologically relevant experimental system for studying MASLD progression, identifying therapeutic targets and evaluating antifibrotic interventions.

Lifestyle-Based Multimodal Prevention Strategies for Alzheimer’s Disease : Curr Alzheimer Res | May 2026

Introduction Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by complex interactions among genetic susceptibility, metabolic dysfunction, neuroinflammation and environmental exposures. With currently available pharmacotherapies offering only modest disease modification, attention has shifted toward preventive lifestyle-based interventions targeting multiple biological pathways involved in cognitive decline. Problem Statement Single-domain interventions such as isolated dietary modification or exercise alone may provide limited protection against neurodegeneration. A major challenge in preventive neurology is defining integrated multimodal strategies capable of simultaneously addressing metabolic, inflammatory, vascular and neurodegenerative mechanisms underlying Alzheimer’s disease progression. Summary This comprehensive review proposes a multidomain framework for Alzheimer’s prevention integrating physical activity, nutrition, intermittent fasting, sleep optimization and gut microbiome modulation. Exercise emerged as a central neuroprotective intervention, with aerobic and resistance training shown to enhance hippocampal neurogenesis, synaptic plasticity and neuronal resilience through activation of BDNF–TrkB signaling and exercise-induced myokines such as IGF-1 and cathepsin B. Dietary approaches including Mediterranean, MIND and ketogenic diets demonstrated potential to reduce oxidative stress, improve mitochondrial efficiency and attenuate amyloid-related neurotoxicity, particularly in metabolically vulnerable APOE4 carriers. Intermittent fasting was highlighted as an additional metabolic intervention capable of promoting ketone utilization, autophagy activation and angiogenesis while simultaneously reshaping gut microbial composition. The review also underscores the growing importance of the gut–brain axis, where microbial metabolites including short-chain fatty acids and tryptophan derivatives may modulate neuroinflammation and neuronal survival. Sleep quality, particularly preservation of slow-wave sleep architecture, was identified as another key determinant of cognitive health through facilitation of glymphatic clearance of amyloid-β and tau proteins. Importantly, the authors emphasize that these interventions likely exert synergistic rather than isolated effects, supporting a precision lifestyle medicine approach for dementia prevention. The review also identifies major research gaps, including optimal intervention intensity, long-term adherence strategies and individualized protocols for genetically high-risk populations.

Fractalkine mRNA-LNPs Enable In Vivo CD8 T-Cell Reprogramming : Sci Immunol | May 2026

Introduction Adoptive cellular immunotherapies have transformed cancer treatment, but current strategies generally require ex vivo cell engineering, manufacturing complexity and individualized processing. The ability to selectively reprogram cytotoxic effector CD8 T cells directly in vivo represents a major next frontier in immunotherapy and RNA-based medicine. Problem Statement Existing lipid nanoparticle (LNP) platforms lack precise targeting specificity for cytotoxic effector T-cell subsets, limiting their ability to selectively manipulate immune responses in vivo. Developing efficient, transient and clinically scalable approaches for targeted CD8 T-cell reprogramming remains a critical unmet challenge in immunotherapy. Summary This study introduces a highly innovative ligand-directed mRNA-LNP platform capable of selectively targeting CX3CR1-positive cytotoxic effector CD8 T cells in vivo using fractalkine (CX3CL1)-conjugated nanoparticles. By exploiting the natural interaction between fractalkine and the CX3CR1 receptor expressed on effector T cells, the investigators achieved remarkably efficient and selective mRNA delivery in both murine models and nonhuman primates. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of circulating and splenic effector CD8 T cells, enabling successful transient cellular reprogramming. Delivery of IL-2–encoding mRNA induced robust exogenous IL-2 secretion, while CD62L-encoding mRNA restored lymphoid homing receptor expression on differentiated effector cells. Importantly, the platform demonstrated impressive translational potential in rhesus macaques, where nearly all peripheral effector CD8 T cells were successfully targeted and reprogrammed to express human CD62L, including trafficking into lymphoid tissues. The work establishes proof-of-concept that endogenous immune cells can be rapidly modified in vivo without ex vivo manipulation or viral engineering. The transient nature of mRNA expression may also offer important safety advantages compared with permanent genetic modification approaches. Beyond oncology, this platform may have broad applications in infectious disease, vaccine development, autoimmunity and immune modulation. Overall, the study represents a major advance in targeted RNA therapeutics and demonstrates the feasibility of highly selective in vivo immune-cell engineering using receptor ligand–guided mRNA nanoparticle technology.

circPLCE1 Loss Drives Fibrosis in Crohn’s Disease : Gut | May 2026

Introduction Intestinal fibrosis is a major complication of Crohn’s disease, frequently leading to strictures, bowel obstruction and surgery. While fibroblast activation is central to fibrogenesis, the metabolic pathways driving intestinal fibrosis remain poorly understood. Emerging evidence suggests that metabolic reprogramming and non-coding RNAs critically regulate fibrotic responses across multiple organs. Problem Statement There are currently no effective antifibrotic therapies for Crohn’s disease. The molecular mechanisms linking fibroblast metabolism, extracellular matrix production and intestinal fibrogenesis remain incompletely defined. Identifying metabolic regulators and upstream non-coding RNA pathways could uncover novel biomarkers and therapeutic targets for fibrostenotic Crohn’s disease. Summary This elegant translational study identifies pentose phosphate pathway (PPP) activation as a metabolic hallmark of fibroblasts in Crohn’s disease–associated intestinal fibrosis. Through integrated metabolomics, single-cell RNA sequencing and spatial transcriptomics, the investigators demonstrated marked upregulation of PPP activity within fibrotic intestinal fibroblasts, particularly involving the xylulokinase (XYLB)-xylulose-5-phosphate (Xu5P) axis. Xu5P promoted extracellular matrix synthesis by epigenetically enhancing collagen gene transcription through increased H3K27 acetylation and reduced H3K27 trimethylation at collagen loci. Mechanistically, the circular RNA circPLCE1 emerged as a critical antifibrotic regulator. CircPLCE1 expression was significantly reduced in strictured Crohn’s disease tissue and inversely correlated with fibrosis severity, bowel wall thickness and magnetic resonance fibrosis markers. Functional studies showed that circPLCE1 directly binds XYLB and competitively suppresses its enzymatic activity. Loss of circPLCE1 restored XYLB function, increased Xu5P accumulation, amplified PPP and glycolytic flux, enhanced NADPH production and accelerated fibrogenesis both in vitro and in vivo. Fibroblast-specific circPLCE1 knockdown aggravated intestinal fibrosis in murine models, whereas circPLCE1 restoration attenuated fibrotic injury. Importantly, inhibition of XYLB reversed the profibrotic metabolic phenotype induced by circPLCE1 loss, confirming XYLB as the critical downstream effector. These findings establish a novel circPLCE1/XYLB/Xu5P metabolic regulatory axis driving intestinal fibrosis in Crohn’s disease and provide compelling mechanistic support for targeting fibroblast metabolism as a future antifibrotic strategy

Regulatory T Cells as a Double-Edged Sword in Cancer Immunotherapy : Annals of Oncology | May 2026

Introduction Regulatory T cells (Tregs) are central mediators of immune tolerance and immune homeostasis. In cancer, however, these same suppressive functions are frequently exploited by tumors to evade antitumor immunity, making Tregs an increasingly important therapeutic target in modern immuno-oncology. Problem Statement Although depletion or functional inhibition of Tregs can enhance antitumor immune responses, indiscriminate disruption of Treg biology risks severe immune-related toxicities and systemic autoimmunity. The challenge is therefore to selectively target intratumoral Tregs while preserving peripheral immune tolerance. Summary This comprehensive review examines the evolving role of Treg-directed therapies in cancer immunotherapy and highlights both the therapeutic promise and biologic complexity of this strategy. Intratumoral Tregs suppress cytotoxic antitumor responses through multiple mechanisms, including IL-10 and TGF-β secretion, IL-2 consumption, metabolic competition, and inhibitory receptor signaling via CTLA-4, TIGIT and related checkpoints. High Treg infiltration is generally associated with poor clinical outcomes across many solid tumors, although prognostic implications vary by tumor type and immune contexture. Advances in single-cell and spatial profiling have demonstrated that tumor-associated Tregs possess distinct transcriptional, metabolic and spatial programs compared with peripheral Tregs, including enrichment of FOXP3+Helios+CCR8+ phenotypes that may serve as biomarkers and therapeutic targets. Current therapeutic approaches fall into three principal categories: direct depletion strategies using antibodies against CD25, CCR4 or CCR8; functional inhibition through checkpoint blockade targeting CTLA-4 or TIGIT; and disruption of metabolic pathways supporting Treg fitness, including PI3K and adenosine signaling. Novel IL-2 variants designed to preferentially modulate effector immune cells while limiting Treg expansion are also under active investigation. Despite encouraging preclinical activity, clinical translation has been complicated by narrow therapeutic windows and high-grade immune toxicities resulting from systemic immune dysregulation. Emerging strategies therefore focus on selectively impairing intratumoral Tregs while sparing systemic immune control, often through combinatorial approaches with PD-1 or PD-L1 blockade. The review emphasizes that deeper understanding of Treg heterogeneity, tissue-specific biology and metabolic dependencies will be essential for developing safer and more effective next-generation cancer immunotherapies.

Metformin Reframed as a Gut-Targeted Mitochondrial Therapy for Glycaemic Control : Nat Metab | May 2026

Introduction Metformin remains the cornerstone first-line therapy for type 2 diabetes mellitus, yet its dominant therapeutic mechanism has remained controversial for decades. While traditional models emphasized hepatic gluconeogenesis suppression, emerging evidence increasingly points toward the intestine as a central therapeutic site of action. Problem Statement The concentrations required for direct mitochondrial complex I inhibition are generally achieved in the intestine rather than the liver during standard metformin dosing, raising uncertainty regarding the true biologic target responsible for metformin-induced glucose lowering, enhanced intestinal glucose uptake and postprandial glycaemic control. Summary This landmark study demonstrates that metformin exerts its principal glucose-lowering effects through selective inhibition of mitochondrial complex I within intestinal epithelial cells. Using human metabolomic datasets and genetically engineered mice expressing metformin-resistant yeast NDI1 specifically in intestinal epithelium, the investigators established that intestinal complex I inhibition is essential for multiple hallmark clinical effects of metformin. Mechanistically, metformin transformed the intestine into a high-capacity glucose disposal organ by increasing intestinal glucose uptake, accelerating glycolysis and promoting conversion of glucose into lactate and lactoyl-phenylalanine. Metformin also suppressed citrulline synthesis, a mitochondrial-dependent metabolic process unique to small intestinal epithelium, providing a clinically measurable biomarker of intestinal mitochondrial inhibition. Importantly, resistance to intestinal complex I inhibition markedly attenuated metformin-induced improvements in glucose tolerance, postprandial glycaemia and pyruvate tolerance in both lean and obese mice. The study further demonstrated that metformin’s efficacy depends on repeated acute bolus exposure rather than cumulative chronic metabolic remodeling, supporting the clinical importance of mealtime dosing. Beyond metformin, phenformin and berberine were shown to share the same intestine-specific mitochondrial complex I–dependent mechanism, suggesting a broader therapeutic paradigm centered on gut-restricted mitochondrial modulation. These findings substantially redefine metformin pharmacology by shifting the primary mechanistic focus from hepatic gluconeogenesis toward intestinal mitochondrial bioenergetics and glucose disposal. The work also opens new avenues for development of gut-selective mitochondrial therapeutics aimed at optimizing glycaemic control while minimizing systemic toxicity.

Histone H4 Dopaminylation Emerges as a Novel Epigenetic Regulator of Tumor Growth : Nat Chem Biol | May 2026

Introduction Post-translational modifications are fundamental regulators of gene expression, chromatin organization and cellular behavior. Dopaminylation, a recently identified modification involving covalent attachment of dopamine to glutamine residues on proteins, has emerged as a novel signaling mechanism, although its biologic functions and substrate landscape remain poorly understood. Problem Statement The absence of robust methods to comprehensively identify dopaminylated proteins has limited understanding of how dopamine-mediated protein modification influences transcriptional regulation and cancer biology. Whether dopaminylation participates directly in epigenetic control mechanisms and tumor growth regulation has remained largely unknown. Summary This study introduces a chemoproteomic platform capable of systematically identifying dopaminylated proteins and substantially expands the known dopaminylation landscape. Using an alkyne-functionalized dopamine probe, the investigators identified more than a thousand putative dopaminylated proteins and characterized histone H4 dopaminylation at glutamine 27 as a previously unrecognized epigenetic modification. Functional analyses demonstrated that H4Q27 dopaminylation acts as a transcriptional repressor in neuroblastoma cells by inhibiting binding of the transcription factor CEBPD at the CCND1 promoter, leading to cyclin D1 suppression and reduced cellular proliferation. These findings establish a direct mechanistic link between dopamine-associated protein modification and chromatin-mediated control of tumor growth. Importantly, the work extends the biologic significance of dopamine beyond neurotransmission and suggests that dopaminylation may represent a broader regulatory system influencing transcriptional programs, cell-cycle progression and oncogenesis. The large-scale substrate dataset generated in this study also provides a major resource for future exploration of dopamine-mediated signaling across multiple physiologic and disease contexts. Overall, this research identifies dopaminylation as an emerging epigenetic mechanism with potential implications for cancer biology and future therapeutic targeting.

Two Decades of PARP Inhibitor Synthetic Lethality Redefined Precision Oncology : Nature | May 2026

Introduction The discovery of synthetic lethality between BRCA1/BRCA2 deficiency and PARP inhibition fundamentally transformed cancer therapeutics and became one of the defining advances in modern precision oncology. By selectively targeting DNA repair vulnerabilities in tumor cells, PARP inhibitors established a new paradigm in which inherited or acquired genomic defects could guide highly personalized cancer treatment. Problem Statement Before the development of PARP inhibitors, targeted cancer therapies largely focused on directly inhibiting activated oncogenic drivers. However, many tumor suppressor gene alterations, including BRCA1 and BRCA2 loss, were considered therapeutically “undruggable.” A major challenge was determining whether vulnerabilities created by defective DNA repair pathways could be exploited therapeutically without excessive toxicity to normal tissues. Summary This perspective reviews the scientific and clinical evolution of PARP inhibitor synthetic lethality over the past two decades and highlights its transformative impact on oncology. The original observation that PARP inhibition selectively kills BRCA-deficient cells established the first successful therapeutic strategy directly linked to a germline biomarker and fundamentally changed treatment approaches in breast, ovarian, prostate and pancreatic cancers. Beyond improving survival, PARP inhibitors also demonstrated that targeting DNA repair dependency could achieve meaningful efficacy with comparatively favorable tolerability. Importantly, the clinical success of PARP inhibitors extended the role of BRCA testing from hereditary cancer risk assessment to routine therapeutic decision-making, embedding germline genetics into mainstream oncology practice. The article also emphasizes the broader biologic significance of synthetic lethality, showing how functional redundancies within tumor cells create exploitable therapeutic dependencies. This concept has since driven extensive efforts to identify additional synthetic lethal interactions across cancer biology. At the same time, the review acknowledges ongoing challenges, including resistance mechanisms, incomplete biomarker precision and variability in response beyond canonical BRCA-mutated tumors. Overall, the PARP inhibitor story represents a landmark example of translational medicine in which fundamental biologic discovery directly reshaped cancer care and established synthetic lethality as a central framework for future targeted therapy development.

Repurposing Legacy Cytotoxics May Define the Next Generation of ADCs : Trends in Cancer | May 2026

Introduction Antibody–drug conjugates (ADCs) have transformed oncology by enabling selective delivery of potent cytotoxic agents directly to tumor cells. Recent successes, particularly with trastuzumab deruxtecan, have expanded the role of ADCs across multiple solid tumors and validated the concept of targeted payload delivery as a major therapeutic platform. Problem Statement Despite rapid clinical expansion, most ADC development programs increasingly rely on a narrow group of payload classes—primarily topoisomerase I inhibitors and microtubule toxins. This mechanistic convergence raises concerns regarding overlapping toxicities, emerging cross-resistance and limited innovation in payload diversity. At the same time, many historically abandoned cytotoxic agents may have failed not because of inadequate antitumor activity, but because systemic exposure rendered them intolerable as free drugs. Summary This perspective proposes a major conceptual shift in ADC development by advocating systematic repurposing of legacy cytotoxic compounds as next-generation ADC payloads. Using trastuzumab deruxtecan as the central model, the authors argue that ADC success depends less on maximal intrinsic potency and more on pharmacologic compatibility with targeted delivery. They introduce a five-pillar framework for payload selection emphasizing proliferation-restricted cytotoxicity, pharmacokinetic “softness,” sustained intracellular target engagement and controlled bystander effects rather than ultrapotent lethality alone. The review highlights multiple underexplored payload classes—including antifolates, nucleoside analogs, kinesin spindle protein inhibitors, noncamptothecin topoisomerase inhibitors and DNA intercalators—that may become clinically viable when delivered through antibody-directed platforms. Importantly, many of these compounds already possess substantial historical pharmacology and toxicity data, potentially accelerating translational development. The authors also emphasize that future ADC innovation will require broader mechanistic diversification to avoid class-wide resistance and toxicity saturation associated with current TOP1-dominant strategies. Overall, this article reframes ADC payload discovery from a potency-driven paradigm toward a systems-level pharmacologic design strategy focused on tumor-selective exposure and biologic precision.

Cytotoxic Tissue-Resident NK Cells Show Potent Antitumor Activity in Solid Tumors : Science Translational Medicine | May 2026

Introduction Natural killer (NK) cell–based immunotherapy has emerged as a promising strategy in cancer treatment because of its ability to mediate tumor killing without prior antigen sensitization. However, clinical efficacy in solid tumors has remained limited, largely due to poor tumor infiltration, immune suppression within the tumor microenvironment and uncertainty regarding the most therapeutically effective NK-cell subsets. Problem Statement Conventional ex vivo expanded NK cells often fail to adequately infiltrate and persist within solid epithelial tumors, reducing their therapeutic effectiveness. At the same time, tissue-resident NK (trNK) cells represent a biologically diverse population, with some subsets demonstrating immunosuppressive properties while others appear highly cytotoxic. Identifying and selectively expanding the most effective antitumor trNK population remains a major challenge in adoptive NK-cell therapy. Summary This translational study identifies a distinct population of highly cytotoxic tissue-resident NK cells characterized by coexpression of CD39, CD49a and CD103, termed cytotoxic trNK (ctrNK) cells, with potent activity against solid epithelial tumors. Using multiomic characterization, the investigators demonstrated that these ctrNK cells possess enhanced tumor-killing capacity, superior migration into tumor organoids and markedly improved control of solid tumors in vivo compared with conventionally activated peripheral NK cells. Importantly, the enhanced antitumor activity appeared linked not only to cytolytic function but also to improved tissue infiltration and retention within the tumor microenvironment, partly mediated through CD103-associated epithelial adhesion mechanisms. A particularly significant finding was that exposure to epithelial tumor cells during ex vivo expansion could drive differentiation toward this highly cytotoxic tissue-resident phenotype, creating a potentially scalable platform for adoptive immunotherapy. These findings directly address one of the major barriers in solid tumor immunotherapy—the inability of transferred immune cells to effectively penetrate and function within immunosuppressive tumor environments. The study positions ctrNK cells as a promising next-generation cellular therapy platform for solid malignancies and provides an important biologic framework for refining NK-cell engineering and expansion strategies in cancer immunotherapy.

Centenarians and the Secret of a Youthful Immune System: Nat Rev Immun | May 2026

Introduction Ageing is typically associated with declining immune function (immunosenescence) and chronic low-grade inflammation (inflammageing), leading to increased susceptibility to infections, cancer, and metabolic diseases. However, centenarians—individuals aged 100 years or more—represent a unique population that defies this paradigm by maintaining relatively preserved immune function and delaying major age-related diseases. Problem Statement The key question is: Why do centenarians escape the typical trajectory of immune decline seen in ageing? Understanding the mechanisms behind their preserved immunity could unlock strategies to improve healthspan and prevent age-related diseases in the general population. Summary This review highlights that centenarians maintain a balanced and resilient immune system across both innate and adaptive compartments. Unlike typical ageing, they demonstrate reduced chronic inflammation, partly due to lower activation of inflammatory pathways such as the NLRP3 inflammasome and a more controlled senescence-associated secretory phenotype. Protective mechanisms include enhanced autophagy, which helps clear damaged cellular components, and preservation of immune cell function resembling that of younger individuals. Omics studies reveal youth-like gene expression patterns, favourable epigenetic profiles, and beneficial gut microbiome composition, all contributing to immune stability. Interestingly, semi-supercentenarians and supercentenarians show even stronger preservation of these features, suggesting that successful ageing involves active biological adaptation rather than passive decline. Overall, centenarians achieve longevity through immune homeostasis, reduced inflammageing, and coordinated molecular adaptations, offering a potential blueprint for therapies aimed at extending healthy lifespan.

TAK1 Blockade May Turn “Cold” Pancreatic Cancer Immunologically Hot: Gastroenterology | May 2026

Introduction and Summary Pancreatic ductal adenocarcinoma remains one of the most immunotherapy-resistant gastrointestinal cancers. A major reason is its dense, immunologically “cold” tumour microenvironment, where cytotoxic T cells are either absent, excluded, or functionally impaired. Despite strong biological rationale, attempts to target the TGF-β pathway to reverse this immune suppression have not yet translated into meaningful clinical success. This study identifies TGF-β-activated kinase 1, also known as TAK1 or MAP3K7, as a key tumour-intrinsic driver of immune resistance in pancreatic cancer. The authors show that TAK1 is aberrantly activated in pancreatic cancer cells and is linked to poor T-cell activity within the tumour microenvironment. Using human pancreatic cancer samples, tumour–T–cell co-culture systems, genetically engineered mouse models, single-cell RNA sequencing, flow cytometry, multiplex immunohistochemistry, proteomics, and mechanistic assays, the study demonstrates that blocking TAK1 induces DNA damage within tumour cells, causes cytoplasmic DNA leakage, and activates the cGAS–STING innate immune pathway. This creates a more inflammatory tumour environment, promotes effector T-cell infiltration, and makes pancreatic tumours more responsive to immune checkpoint blockade. Problem Statement Immune checkpoint inhibitors have transformed several solid tumours, but they have had limited benefit in pancreatic ductal adenocarcinoma. The central challenge is not simply the absence of immune therapy, but the inability of pancreatic tumors to generate a sufficiently inflamed, T-cell-rich microenvironment. TGF-β pathway inhibition has been explored as a strategy to reverse immune suppression, but clinical results have been disappointing. Therefore, there is a need to identify more precise, tumor-specific nodes within this pathway that can convert pancreatic cancer from an immune-resistant tumor into one that is vulnerable to immunotherapy. This study proposes TAK1 as one such target. Key Findings for Clinicians The study shows that TAK1 is activated within pancreatic cancer cells and appears to contribute to T-cell dysfunction in the tumor microenvironment. When TAK1 was inhibited pharmacologically using Takinib, or genetically deleted in pancreatic cancer mouse models, tumors showed increased infiltration of CD4+ and CD8+ effector T cells. Importantly, TAK1 blockade made pancreatic tumors more sensitive to immune checkpoint blockade, suggesting that TAK1 inhibition may act as an immune-sensitizing strategy rather than a simple cytotoxic approach. Mechanistically, TAK1 inhibition caused DNA damage in cancer cells. Damaged DNA leaked into the cytoplasm, where it activated the cGAS–STING pathway, a key innate immune sensing mechanism that promotes inflammatory signaling and adaptive immune recruitment. The study also identifies a molecular repair axis involving TAK1, EphA2, and RAD51. TAK1 phosphorylates EphA2 at serine 897, which then contributes to phosphorylation of RAD51 at tyrosine 315. RAD51 is a major DNA repair protein involved in homologous recombination. In simple terms, TAK1 helps pancreatic cancer cells preserve genomic integrity and avoid immune activation. By blocking TAK1, the tumor cell loses part of its DNA repair protection, accumulates DNA damage, activates innate immune sensing, and becomes more visible to the immune system. Clinical Relevance This is a highly relevant translational study because it addresses one of the most important barriers in pancreatic cancer treatment: resistance to immunotherapy. The findings suggest that pancreatic cancer immune resistance may be partly maintained by tumor-intrinsic TAK1 activity. Rather than only targeting the surrounding stroma or immune cells, this approach targets the cancer cell itself and forces it to generate an inflammatory danger signal through DNA damage and cGAS–STING activation. For clinicians, the most important message is that TAK1 inhibition may potentially convert pancreatic cancer from an immune-cold to an immune-inflamed phenotype, thereby creating a biological rationale for combining TAK1 blockade with immune checkpoint inhibitors. This could be especially relevant in future therapeutic strategies where TAK1 activity, EphA2 signaling, RAD51-mediated DNA repair, or cGAS–STING activation may serve as biomarkers for patient selection. Limitations and Caution This is not yet a clinical practice-changing study. The work is primarily basic and translational, supported by human tissue analysis, in vitro experiments, and genetically engineered mouse models. The therapeutic effect of TAK1 inhibition in human pancreatic cancer patients remains unproven. The safety, dosing, toxicity profile, and therapeutic window of TAK1 inhibitors will require careful evaluation, particularly because TAK1 has important biological functions in inflammatory and survival pathways. It is also unclear whether all pancreatic cancers will respond similarly. PDAC is molecularly and immunologically heterogeneous, and only selected tumors may be vulnerable to TAK1-directed immune sensitization. Finally, activation of cGAS–STING biology can be context-dependent. While it may promote anti-tumor immunity, excessive or chronic pathway activation may have complex effects that need further study. Conclusion This study identifies TAK1 as a critical tumor-intrinsic regulator of DNA repair, immune evasion, and checkpoint inhibitor resistance in pancreatic cancer. By inhibiting TAK1, pancreatic cancer cells develop DNA damage, activate the cGAS–STING pathway, recruit effector T cells, and become more responsive to immune checkpoint blockade in preclinical models. The study provides a strong biological rationale for future development of TAK1-targeted combination therapy with immunotherapy in pancreatic ductal adenocarcinoma. However, clinical validation is essential before this approach can be considered for patient care.

Role of Innate Oral Immunity and Salivary Fluid in IBD: CMGH | April 2026

Introduction Inflammatory bowel disease is increasingly understood as a disorder shaped not only by the gut itself, but also by extraintestinal immune and microbial influences. The oral cavity is one such important site because it is closely linked to the gut through swallowed saliva, oral microbes, and immune mediators. While the contribution of oral adaptive immunity and oral dysbiosis to IBD has been explored previously, the role of oral innate immunity, especially salivary fluid and its bioactive components, has remained unclear. This study examined whether saliva influences the oral microbiome, gut microbiome, gut barrier, and the course of colitis. Problem statement The key unanswered question was whether salivary innate immunity protects the gut or worsens intestinal inflammation, and through what mechanism this effect occurs. Summary This study showed that saliva has surprisingly little influence on the oral microbiome, but it has a clear effect on the gut environment and the severity of colitis. Using two mouse models with reduced salivation, the authors found that lack of saliva delayed the early development of DSS-induced colitis, suggesting that some salivary factors may initially worsen inflammation. However, once disease progressed, these mice developed rapid weight loss and higher mortality, indicating that saliva also contains protective components essential for later gut stability and survival. The most important mechanistic insight was that saliva acts mainly through the gut barrier rather than by major reshaping of the microbiome. Mass spectrometry identified two key salivary molecules with opposing roles. Trefoil factor 2 (TFF2) acted as a protective peptide, helping preserve gut barrier integrity and reducing colitis severity. In contrast, macrophage migration inhibitory factor (MIF) acted as a damaging cytokine that worsened inflammation. Neutralizing TFF2 aggravated colitis, whereas neutralizing MIF was protective. Overall, the study proposes that oral innate immunity is an important upstream regulator of gut inflammation. Saliva is not merely a digestive fluid; it carries immunologically active molecules that can either protect or damage the intestine depending on the disease stage. Clinically, this opens an interesting therapeutic concept: reducing salivary MIF or enhancing TFF2 may become a novel strategy for IBD treatment.

Microbiota–Inflammasome Axis: Gut | April 2026

Introduction The gastrointestinal tract functions as a highly integrated system where digestion, immunity, and metabolic regulation are closely linked to the gut microbiota. This vast microbial ecosystem plays a central role in maintaining mucosal integrity, immune balance, and systemic homeostasis. A key emerging regulator in this interaction is the inflammasome, a multiprotein complex that senses microbial and cellular danger signals and orchestrates innate immune responses. The microbiota–inflammasome axis has recently gained attention as a crucial bridge connecting gut health with systemic diseases, including cancer, metabolic disorders, and neurological conditions. Problem Statement Despite growing recognition of the microbiota’s role in disease, the precise mechanisms through which dysbiosis triggers pathological immune activation remain incompletely understood. In particular, the role of inflammasomes as central mediators of microbiota-driven inflammation is underexplored. This gap limits our ability to translate microbiome science into targeted therapies, especially in complex diseases such as inflammatory bowel disease, gastrointestinal cancers, and neuroinflammatory disorders. Summary This review highlights that dysbiosis can aberrantly activate inflammasomes, disrupting gut homeostasis and promoting chronic inflammation. The microbiota–inflammasome axis influences not only gastrointestinal diseases but also systemic conditions via pathways such as the gut–brain axis, including vagal signaling and neuroendocrine responses. Importantly, inflammasome-mediated cytokines act as key messengers linking gut-derived signals to distant organs. Emerging evidence also demonstrates a role in cancer progression and immune modulation. The integration of artificial intelligence is accelerating understanding of these complex interactions, enabling biomarker discovery and therapeutic targeting. Overall, the microbiota–inflammasome axis represents a promising frontier for precision medicine across gastrointestinal and systemic diseases.

Non-invasive Assessment of Gut Barrier Function in Environmental Enteropathy Using TFS: Gut | April 2026

Introduction Undernutrition remains a major global health challenge, particularly in low-resource settings, and is closely linked to a complex gut disorder known as environmental enteropathy (EE). EE is characterised by impaired intestinal barrier function (“leaky gut”), inflammation, and reduced nutrient absorption, which together limit the effectiveness of nutritional interventions. Accurate assessment of intestinal permeability is therefore crucial, but existing methods such as lactulose: rhamnose (LR) testing are cumbersome, invasive, costly, and difficult to implement at scale. Problem Statement Current diagnostic tools for evaluating gut barrier dysfunction in EE lack feasibility for widespread clinical and field use, especially in vulnerable populations like children and those in resource-limited regions. There is an urgent need for a rapid, reliable, non-invasive, and scalable method to assess intestinal permeability and overall gut function. Summary This study introduces transcutaneous fluorescence spectroscopy (TFS), a novel, non-invasive, sample-free technique that measures intestinal permeability through skin-based detection of fluorescent markers. TFS successfully differentiated increased gut permeability in Zambian participants with EE compared to healthy UK controls and showed a strong correlation with the conventional LR test (r≥0.78). Importantly, TFS allows simultaneous assessment of intestinal barrier integrity and gastric emptying without the need for biological sample collection. These findings position TFS as a promising tool for large-scale, real-time monitoring of gut health, particularly in low-resource settings, with potential applications beyond EE, including IBD and coeliac disease.

Dengue Suppression by Male Wolbachia-Infected Mosquitoes: NEJM | March 2026

Introduction Dengue continues to emerge as a major global public health challenge, driven by rapid urbanisation, climate change, and the expansion of mosquito habitats. Conventional vector-control strategies such as insecticides, source reduction, and repellents have shown limited and often unsustained impact, while vaccine options remain suboptimal across all serotypes. This has led to growing interest in biologically innovative approaches. One such strategy involves infecting male Aedes aegypti mosquitoes with Wolbachia bacteria, which induces cytoplasmic incompatibility and prevents viable offspring when these males mate with wild-type females, thereby suppressing mosquito populations and potentially reducing dengue transmission. Problem Statement Despite multiple preventive strategies, dengue incidence continues to rise globally, highlighting a critical gap in effective, scalable, and sustainable vector-control interventions. While Wolbachia-based methods have shown promise in observational and limited trials, robust randomised evidence demonstrating real-world epidemiologic benefit—particularly using male-only sterile mosquito release (IIT-SIT approach)—has been lacking. Summary This large cluster-randomised trial in Singapore demonstrated that releasing Wolbachia-infected male mosquitoes significantly reduced both mosquito density and dengue incidence. Female mosquito abundance dropped markedly in intervention areas, and dengue positivity rates decreased from 21% in control clusters to 6% in intervention clusters. The intervention achieved a protective efficacy of approximately 71–72% after sustained exposure. These findings provide strong real-world evidence that Wolbachia-based vector suppression is an effective, environmentally sustainable strategy for dengue control. This approach represents a major shift from chemical-based control toward biological population suppression, with potential scalability in urban settings worldwide.

Molecularly Guided Therapy in HCC: Journal of Hepatology | March 2026

Introduction Advanced primary liver cancers, including hepatocellular carcinoma and cholangiocarcinoma, remain difficult to treat once they become refractory to standard systemic therapies. Survival outcomes are poor, and therapeutic options are limited, particularly in heavily pretreated patients. With the growing understanding of tumor biology, comprehensive genomic profiling has emerged as a promising strategy to identify actionable molecular targets and guide personalized therapy, but its real-world clinical utility in liver cancers has remained uncertain. Problem Statement Although next-generation sequencing is increasingly used, standard panels often fail to detect a significant proportion of actionable alterations. Moreover, it is unclear whether identifying such alterations truly translates into meaningful clinical benefit, especially in patients who have already failed multiple lines of therapy. Summary This multicenter French initiative demonstrates that comprehensive genomic profiling using whole-genome, whole-exome, and RNA sequencing is feasible in advanced liver cancers and identifies actionable alterations in nearly two-thirds of patients. Importantly, this approach detects more targets than conventional sequencing panels. Matched targeted therapies based on ESCAT I–III alterations led to meaningful disease control in a subset of patients, particularly in cholangiocarcinoma and combined tumors, with significantly improved progression-free survival. In contrast, no benefit was observed when therapies were guided by lower-evidence ESCAT IV alterations. These findings highlight that the clinical value of precision oncology depends not only on identifying mutations but also on the level of evidence supporting their actionability. Early genomic profiling may allow better patient selection, preserve liver function, and expand access to effective targeted therapies in advanced hepatobiliary cancers.

Berberine and Cholestatic Liver Disease: Clinical and Molecular Hepatology | March 2026

Introduction Cholestatic liver disease (CLD) is a progressive condition characterised by impaired bile formation and flow, leading to bile accumulation, liver injury, and eventual cirrhosis or liver failure. Despite advances in hepatology, treatment options remain limited, with ursodeoxycholic acid and obeticholic acid offering only partial benefit. Increasing attention has been directed toward the gut–liver axis, particularly the role of gut microbiota and their metabolites in modulating liver disease. Problem Statement The key mechanisms driving CLD progression remain incompletely understood, and current therapies fail to adequately halt disease progression in many patients. Although berberine has shown hepatoprotective effects, its very low systemic bioavailability raises uncertainty about how it exerts clinical benefit, suggesting an indirect mechanism possibly mediated through gut microbiota. Summary This study demonstrates that orally administered berberine is converted by gut microbiota into dihydroberberine, which acts as the active metabolite. Dihydroberberine suppresses serotonin (5-HT) production in intestinal enterochromaffin cells by inhibiting tryptophan hydroxylase 1, thereby disrupting the 5-HT signalling axis involved in cholestatic injury. This mechanism was consistently validated across multiple animal models and further supported by clinical data showing improved biochemical markers and reduced 5-HT levels in patients. These findings highlight a novel microbiota-driven therapeutic pathway, positioning berberine as a promising candidate in CLD management.

Obesity and Cancer: JAMA March 2026

Obesity is no longer viewed only as a metabolic disorder; it is now a major cancer-promoting state. This review explains how excess adiposity drives cancer through intertwined biologic pathways including chronic inflammation, hormonal dysregulation, immune suppression, altered energy metabolism, DNA damage, and gut microbiome disruption. For clinicians, the key message is practical: obesity is a modifiable cancer risk factor, and meaningful weight loss may reduce future cancer burden. Main clinical message Overweight and obesity are associated with higher rates of multiple cancers, especially endometrial, colorectal, liver, gallbladder, pancreas, kidney, postmenopausal breast, oesophagal adenocarcinoma, ovarian, thyroid, gastric, prostate, and multiple myeloma. The review estimates that obesity contributes to about 10% of new cancers annually in the US, and even more in selected tumour types such as endometrial and hepatobiliary malignancies. Key biologic pathways The review highlights 5 major mechanisms: 1. Adipose tissue dysfunction: enlarged adipocytes produce excess estrogens, leptin, inflammatory cytokines, and less adiponectin. 2. Chronic inflammation: IL-6, TNF-α, prostaglandin E2, and related mediators create a pro-tumor microenvironment. 3. Immune escape: obesity impairs cytotoxic T cells and NK cells while increasing immunosuppressive myeloid-derived suppressor cells. 4. Metabolic support for tumors: adipose tissue supplies free fatty acids and other fuel for cancer growth. 5. DNA damage and microbiome changes: oxidative stress and dysbiosis increase genomic instability and mucosal inflammation. Important epidemiologic insights Cancer risk is not determined by BMI alone. Patients with metabolically unhealthy obesity appear to have the highest cancer risk. The review also stresses that childhood and adolescent obesity trajectories may influence cancer risk later in life. Interestingly, obesity increases postmenopausal breast cancer risk, but may show a different association before menopause. Weight loss and cancer prevention The review suggests that modest weight loss may not be enough. A threshold of more than 10% body weight reduction may be needed to produce measurable reductions in obesity-related cancer risk. Observational data suggest benefit with: Bariatric surgery, especially for endometrial cancer risk reduction GLP-1 receptor agonists, with retrospective data suggesting lower incidence of some obesity-related cancers Metformin and related metabolic therapies, though stronger prospective evidence is still needed Practice implications Clinicians should view obesity management as part of long-term cancer prevention, not only cardiovascular and metabolic risk reduction. Counselling should move beyond BMI to include metabolic health, waist circumference, adiposity pattern, and sustained weight-loss strategies. Multimodal care combining lifestyle measures, pharmacotherapy, and in selected patients, bariatric surgery may have future oncologic relevance. Limitations of the review Much of the evidence linking weight loss interventions to lower cancer incidence remains observational, not randomised. Several mechanistic pathways are strongly biologically plausible but not yet fully translated into cancer prevention trials. Bottom line Obesity promotes cancer through multiple biologic pathways, and meaningful sustained weight loss may reduce this risk. This review strengthens the concept that treating obesity is also part of cancer prevention.

PDE5A+ Cancer-Associated Fibroblasts in Gastric Cancer: Gut, March 2026

Introduction Gastric cancer remains one of the most lethal malignancies worldwide. The tumour microenvironment (TME)—particularly cancer-associated fibroblasts (CAFs)—plays a critical role in tumour progression, immune evasion, and resistance to immunotherapy. Although immune checkpoint inhibitors (ICIs) have improved outcomes in some patients with gastric cancer, many fail to respond due to a highly immunosuppressive TME. Understanding the specific fibroblast subpopulations responsible for immune suppression may help identify new therapeutic targets. Summary In this study, researchers used single-cell RNA sequencing and spatial transcriptomics from gastric cancer tissues to identify a distinct fibroblast subset characterized by phosphodiesterase type 5A (PDE5A) expression. Key findings include: PDE5A⁺ CAFs were associated with poorer overall survival and a strongly immunosuppressive tumour microenvironment. These fibroblasts promoted extracellular matrix remodeling and epithelial–mesenchymal transition (EMT) in gastric cancer cells. PDE5A⁺ CAFs activated the PI3K/AKT/mTOR pathway, leading to secretion of CXCL12, which interacts with CXCR4 to recruit dysfunctional CD8⁺ TEX⁺ LAG3 T cells, thereby suppressing effective anti-tumor immunity. Tumors enriched with PDE5A⁺ CAFs showed T-cell exclusion and reduced cytotoxic CD8⁺ T-cell infiltration, contributing to immunotherapy resistance. Importantly, combined therapy using a PDE5A inhibitor (vardenafil) with LAG3 immune checkpoint blockade significantly improved antitumor responses and reduced tumor growth in mouse models. Key Message PDE5A⁺ cancer-associated fibroblasts represent a critical driver of immune suppression in gastric cancer, and targeting this pathway may enhance the effectiveness of immunotherapy.

Bimagrumab + Semaglutide: BELIEVE STUDY: Nature Medicine | 2026

Introduction Most obesity therapies reduce body fat, but they also cause a meaningful loss of lean mass, including skeletal muscle. This matters because preserving muscle is important for physical function, metabolic health, and long-term weight loss. Bimagrumab is an investigational monoclonal antibody that blocks activin type II receptors, promoting fat loss and muscle preservation/growth. Semaglutide, a GLP-1 receptor agonist, mainly reduces weight by lowering appetite and food intake. The BELIEVE phase 2 trial tested whether combining these two drugs could produce greater weight loss with better body composition than either alone. Summary In this randomised phase 2 trial, 507 adults with obesity received placebo, bimagrumab, semaglutide, or combinations for 48 weeks, followed by extension to 72 weeks. At week 48, body weight fell by 9.3 kg with high-dose bimagrumab alone, 14.2 kg with semaglutide 2.4 mg, and 17.8 kg with the high-dose combination, versus 3.3 kg with placebo. By week 72, the high-dose combination achieved about 22.1% weight loss, greater than semaglutide alone. The major strength of the combination was body composition. It produced striking reductions in total fat mass and visceral fat while preserving lean mass far better than semaglutide alone. At week 72, the high-dose combination reduced fat mass by 45.7% and visceral adipose tissue by 58.2%, while limiting lean-mass loss. Glycemic measures, waist circumference, hsCRP, and several metabolic markers also improved. Adverse effects reflected known profiles of both drugs. Bimagrumab was associated with muscle spasms, diarrhea, and acne, while semaglutide caused nausea, diarrhea, constipation, and fatigue. Key Message This study suggests that bimagrumab plus semaglutide may offer a next-generation obesity treatment approach: substantial weight loss with enhanced fat loss and relative preservation of muscle mass.

TAF2 Drives Hepatocyte Survival in HCC: Hepatology March 26

Chromosome 8q amplification, a common genomic alteration in hepatocellular carcinoma (HCC), includes the gene TATA-box binding protein–associated factor 2 (TAF2), a key component of the TFIID basal transcription complex. This study demonstrates that TAF2 is overexpressed in human HCC tissues and cell lines, and higher expression correlates with poorer overall survival. Using hepatocyte-specific TAF2 knockout mice, investigators showed that loss of TAF2 leads to hepatocyte death, compensatory proliferation, inflammation, and fibrosis, creating a microenvironment favorable for tumor development. Consequently, DEN/high-fat high-sugar diet–induced HCC was markedly increased in TAF2-deficient mice. Conversely, TAF2 overexpression alone did not initiate liver tumors, but significantly enhanced MYC-driven hepatocarcinogenesis, suggesting that TAF2 acts as a tumor promoter rather than a primary oncogenic driver. Mechanistically, TAF2 binds promoter regions of tumor-promoting genes and non-coding RNAs, enhancing transcription programs that support cancer hallmarks such as proliferation and survival. Key Message: TAF2 plays a central role in maintaining hepatocyte viability and can accelerate hepatocarcinogenesis in the presence of oncogenic signals, highlighting it as a potential biomarker and therapeutic target in HCC.

In Vivo CRISPR Screens in Gastric Organoids: Gastroenterology | March 2026

Introduction Understanding which genes restrain gastric tumor growth—and how host factors like Helicobacter pylori shape tumor biology—remains central to precision prevention and therapy. CRISPR-Cas9 loss-of-function screening offers a scalable way to discover tumor suppressors, but most screens are performed in vitro and miss key in vivo pressures such as immunity and microbial influences. This study builds an organoid-based in vivo CRISPR platform to identify gastric tumor suppressors in both ectopic (subcutaneous) and orthotopic (stomach) settings. Summary (≈200 words) Using murine gastric organoids, the authors performed in vivo CRISPR knockout screening with (1) a custom library targeting 49 putative gastric tumor suppressors and (2) a genome-scale “cancer” library targeting ~5000 genes. Screens were conducted across immunocompetent and immunodeficient mice, with and without H pylori infection, and in both subcutaneous and surgically implanted orthotopic tumor models. Recurrently enriched guides identified Pten, Fbxw7, and multiple TGF-β pathway components (Smad4, Tgfbr1, Tgfbr2, Acvr2a) as consistent tumor suppressor hits across models; genome-scale screening confirmed these and revealed additional candidates. The top hits were individually validated in vivo. Mechanistically, Pten loss drove large, highly vascular tumors with neutrophil recruitment and T-cell exclusion, highlighting an immune-evasive, pro-angiogenic state. In contrast, loss of Smad4, Tgfbr1, or Acvr2a produced lesions resembling early gastric precancer states, including Alcian blue–positive intestinal metaplasia and compensatory hyperplasia. Notably, H pylori did not change the tumor mutational landscape; instead, it primarily reshaped the tumor microenvironment, promoting influx of tumour-supporting SiglecF⁺ neutrophils. Overall, the work introduces a versatile in vivo organoid-CRISPR platform that separates tumor genetics from host factors while capturing clinically relevant gastric cancer biology.

Understanding Polyposis Development: Gastroenterology | March 26

Introduction Most clinicians recognise classic inherited polyposis syndromes such as familial adenomatous polyposis (FAP) from pathogenic variants in APC, and MUTYH-associated polyposis (MAP) from biallelic MUTYH variants. Yet, a large proportion of patients with 20–100 adenomas (and even some with hundreds) remain “genetically unexplained” after routine multigene panel testing. This editorial discusses why that gap persists and why newer molecular approaches are beginning to close it. Summary Llor reviews major advances that explain previously unresolved polyposis cases. A key theme is that many APC pathogenic alterations are missed by standard testing, including deep intronic variants causing aberrant splicing or pseudoexon formation, synonymous changes that disrupt splicing, large structural rearrangements, and mobile element insertions—often requiring whole-exome/genome sequencing, long-read sequencing, and RNA-based analyses for detection. Another important mechanism is somatic mosaicism, where post-zygotic APC mutations are present only in a subset of tissues; phenotype depends on when the mutation occurs in development and can appear attenuated in the proband but become more severe in offspring if transmitted through germline involvement. Mosaic APC variants may account for a meaningful fraction of “unexplained” FAP-like presentations. The editorial highlights new work by Sommer et al. in this issue, who studied individuals with unexplained adenomatous or serrated polyposis and found APC mosaicism in ~19% of evaluable adenomatous polyposis cases, with additional suspected mosaicism. The broader implication is practical: when multigene panels are negative, clinicians and genetic services should increasingly consider expanded diagnostics that include intronic/regulatory APC alterations and mosaicism testing. Finally, Llor notes that serrated lesions show distinct molecular patterns (often BRAF), but their biology may not mirror adenomatous APC-driven progression; many serrated lesions may represent benign clonal outgrowths requiring additional hits to progress—an area where major mechanistic questions remain.

Single-Cell Multimodal Analysis Reveals the Dynamic Immunopathogenesis of HBV-ACLF: Gut | 2026 | DOI: 10.1136/gutjnl-2024-333308

Introduction Acute-on-chronic liver failure (ACLF) is a highly dynamic and life-threatening syndrome marked by intense systemic inflammation and immune dysregulation. In Asia, hepatitis B virus (HBV) reactivation is a leading trigger of ACLF. However, the longitudinal immune trajectories that drive progression, recovery, or deterioration in HBV-related ACLF (HBV-ACLF) remain poorly defined. This study used single-cell multiomics to map immune evolution during the disease course. Summary In this longitudinal analysis of 17 hospitalised patients with HBV-ACLF and 15 controls, single-cell RNA sequencing and proteomics of peripheral blood mononuclear cells revealed stage-specific immune reprogramming. Early ACLF was characterised by expansion of VCAN⁺CD14⁺ monocytes with activated interferon-stimulated genes, fuelling an inflammatory surge following HBV relapse. As the disease progressed, hyperinflammatory CXCR2⁺ neutrophils and CD163⁺ monocytes became enriched and were strongly associated with deterioration. Cytotoxic T cells were reduced and functionally exhausted in progressive disease, partly driven by immunosuppressive CXCR2⁺ neutrophils. Pharmacologic CXCR2 inhibition reduced neutrophil infiltration and restored cytotoxic T-cell function in experimental models, suggesting therapeutic potential. Six immune cellular modules were identified for patient stratification. CM2 and CM6 predicted adverse outcomes, while CM3 marked a potential early therapeutic window. This study provides a dynamic immune atlas of HBV-ACLF and supports immune-targeted precision strategies for risk stratification and intervention.

UGT1A1 Genotype-Guided Irinotecan Dosing and Survival in Colorectal & Pancreatic Cancer - The Lancet | May 2026

Introduction UGT1A1 poor metabolisers (PMs) are at higher risk of severe irinotecan-related toxicity. A 30% upfront dose reduction is commonly recommended for safety, but whether this compromises survival has remained uncertain. Summary In this Dutch multicentre retrospective cohort (2017–2024), including 779 patients with colorectal or pancreatic cancer, 9.8% were UGT1A1 poor metabolisers who received a 30% reduced irinotecan dose. Progression-free and overall survival were comparable between dose-reduced PMs and fully dosed intermediate/normal metabolisers. Severe toxicity rates were also similar. These findings suggest that genotype-guided dose reduction improves safety without compromising survival, supporting routine UGT1A1-guided irinotecan dosing in clinical practice.

Genetic Landscape of PSVD: Hepatology, Feb.26

Porto-sinusoidal vascular disorder (PSVD) is a rare, non-cirrhotic vascular liver disease characterised by portal venule and sinusoidal abnormalities leading to portal hypertension. Despite its clinical significance, the underlying pathophysiology has remained poorly understood. In this comprehensive review, Ciriaci et al. systematically evaluate genetic mutations associated with PSVD, offering critical insights into its mechanistic basis. The authors identify 34 genes and one chromosomal abnormality previously linked to PSVD and report an additional mutation in TBL1XR1 (Pierpont syndrome). Genetic associations fall into two broad categories: Syndromic PSVD – occurring in multisystem disorders (e.g., telomere biology disorders, immune deficiencies, cystic fibrosis, Williams-Beuren syndrome, Turner syndrome). Isolated PSVD – involving mutations such as KCNN3, DGUOK, GIMAP5, FCHSD1, TRMT5, and HRG. Most cases present clinically with complications of portal hypertension rather than early liver dysfunction. Importantly, gene expression analyses reveal predominant involvement of immune cells, suggesting that immune-mediated vascular remodelling may play a central role in disease development. Pathway analyses further support two mechanistic subtypes: one driven by morphogenetic vascular abnormalities, and another secondary to immune dysregulation. Clinically, the review recommends next-generation sequencing panels for patients with early-onset PSVD, syndromic features, or a family history. This work redefines PSVD as a genetically heterogeneous disorder and highlights immune pathways as promising targets for future research and therapeutic development.

GLP-1 Medicines 2.0: Nature Medicine-Feb. 26

Glucagon-like peptide-1 (GLP-1) receptor agonists have evolved from glucose-lowering agents for type 2 diabetes into transformative therapies reshaping cardiometabolic medicine. In this comprehensive review, Daniel Drucker outlines how GLP-1–based therapies now extend well beyond glycemic control, influencing obesity, cardiovascular disease, peripheral artery disease, obstructive sleep apnea, and potentially multiple non-metabolic disorders. These agents exert benefits through several complementary mechanisms: sustained weight reduction, improved insulin sensitivity, attenuation of systemic inflammation, and direct receptor-mediated effects in diverse tissues. The development of long-acting formulations with optimised pharmacokinetics has amplified weight loss and cardiometabolic benefits. Furthermore, next-generation multi-agonist molecules incorporating additional peptide epitopes (e.g., dual or triple incretin-based constructs) are demonstrating enhanced metabolic efficacy. Importantly, research is expanding into novel indications, including metabolic liver disease, neurodegenerative disorders, substance use disorders, inflammatory bowel disease, arthritis, and even type 1 diabetes. These developments reflect a paradigm shift—from symptom control to disease modification. However, critical questions remain regarding long-term safety, durability of benefit, comparative effectiveness among agents, access inequities, and economic sustainability. In summary, GLP-1 medicines are no longer simply antidiabetic drugs; they represent a rapidly expanding therapeutic platform with multisystem implications. The next decade will determine whether these agents achieve their full potential as cornerstone therapies in metabolic and inflammatory disease management.

Single-Cell Multiomics Maps the Immune Storm Driving HBV-ACLF Progression- Gut Feb.26

This longitudinal single-cell multiomics study provides a detailed immune roadmap of HBV-related acute-on-chronic liver failure (HBV-ACLF), a syndrome marked by profound immune dysregulation and high short-term mortality. Using single-cell RNA sequencing and proteomics from 45 peripheral blood samples (across progressive, stable, and recovering ACLF courses) and appropriate controls, investigators identified a dynamic immune trajectory. Key findings: Early phase (ACLF-1): Expansion of VCAN⁺CD14⁺ inflammatory monocytes driven by HBV relapse. These cells exhibited strong interferon-stimulated gene activation, fueling the early inflammatory storm. Progressive phase: Apoptotic hepatocytes triggered expansion of CXCR2⁺ neutrophils and CD163⁺ monocytes, strongly associated with disease deterioration. Immune exhaustion: Cytotoxic T cells were markedly reduced and functionally impaired in progressive patients. CXCR2⁺ neutrophils demonstrated immunosuppressive activity, directly inducing T-cell exhaustion. Importantly, pharmacologic CXCR2 inhibition in ACLF mouse models reduced neutrophil infiltration, restored cytotoxic T-cell function, and improved outcomes—highlighting a promising therapeutic target. Six immune cellular modules (CMs) were identified for risk stratification, with CM2 and CM6 predicting outcomes, and CM3 suggesting a potential early intervention window. Clinical implication: HBV-ACLF progression is driven by a shift from hyperinflammation to neutrophil-mediated immune paralysis. Targeting the CXCR2 axis may represent a rational strategy for precision immunomodulation in ACLF.

LECT2–PHB2 Signaling: A New Target in Alcohol-Associated Hepatitis

Alcohol-associated hepatitis (AH) remains a high-mortality condition with limited effective therapies. A central driver of disease progression is excessive hepatic inflammation, particularly massive neutrophil infiltration, triggered by cytokine signaling, chemokine release (e.g., CXCL1, CXCL8), endothelial activation, and sterile inflammation mediated by damage-associated molecular patterns such as HMGB1 and mitochondrial DNA. This article highlights a newly described LECT2–PHB2 molecular axis as a mechanistic contributor to inflammatory amplification in AH. Leukocyte cell–derived chemotaxin 2 (LECT2), a hepatokine previously implicated in metabolic and inflammatory liver diseases, appears to interact with prohibitin-2 (PHB2), a mitochondrial and signaling regulator protein. Emerging data suggest that dysregulation of this pathway exacerbates hepatocellular stress responses, enhances inflammatory signaling, and promotes neutrophil recruitment, thereby worsening liver injury. Importantly, the LECT2–PHB2 interaction may represent a novel therapeutic opportunity. Targeting this axis could interrupt the self-sustaining loop of hepatocyte injury and immune activation that characterizes severe AH. Given the limited efficacy of current treatments—largely restricted to corticosteroids in selected patients—identifying pathways that modulate both hepatocellular stress and inflammatory amplification is clinically significant. In summary, the LECT2–PHB2 axis provides fresh mechanistic insight into AH pathogenesis and may offer a promising target for future drug development aimed at reducing inflammation and improving outcomes in this devastating condition.

ER Stress as the Molecular Bridge Between MASH and Hepatocellular Carcinoma- Hepatology Feb.26

Metabolic dysfunction–associated steatohepatitis (MASH) is rapidly becoming a leading driver of hepatocellular carcinoma (HCC). This comprehensive review highlights endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a central molecular link connecting chronic metabolic liver injury to malignant transformation. Hepatocytes are highly dependent on ER function to manage lipid metabolism, protein synthesis, and detoxification. In MASH, excess lipids, oxidative stress, and inflammation overwhelm ER proteostasis, leading to persistent activation of the UPR. While short-term UPR signaling is adaptive, chronic ER stress promotes inflammation, fibrosis, genomic instability, and altered cell death pathways, all of which favor progression toward cirrhosis and HCC. The review details how the three major UPR branches—IRE1/XBP1, PERK/ATF4, and ATF6—exert context-dependent effects across hepatocytes, hepatic stellate cells, endothelial cells, and immune cells. Sustained activation of these pathways reshapes the tumor microenvironment, enhances fibrogenesis, suppresses antitumor immunity, and contributes to resistance to systemic therapies such as sorafenib. ER stress signaling also influences immune evasion through macrophage polarization, dendritic cell dysfunction, and PD-L1 regulation. Importantly, ER stress pathways represent actionable therapeutic targets. Preclinical studies suggest that selectively modulating UPR signaling—either by inhibiting adaptive survival pathways or pushing cells toward terminal stress—may sensitize tumors to chemotherapy and immunotherapy while also limiting fibrosis. In summary, chronic ER stress is a unifying driver of MASH progression and hepatocarcinogenesis. Targeting UPR signaling offers a promising avenue for combination therapies aimed at preventing or treating HCC in patients with metabolic liver disease.

Targeting Caspase-8 to Slow MASH Progression- Hepatology Feb.26

Metabolic dysfunction–associated steatohepatitis (MASH) is driven by oxidative stress, hepatocyte injury, inflammation, and fibrosis. Activation of the c-Jun N-terminal kinase (JNK) pathway has long been associated with MASH, but whether JNK signaling in hepatocytes is harmful or protective has remained uncertain. This study provides an important clarification. Using human genetic data, patient liver samples, and multiple mouse models, the authors show that JNK1/JNK2 signaling in hepatocytes is protective rather than deleterious during MASH progression. In patients, loss-of-function variants in JNK1 were associated with a higher prevalence of steatotic liver disease and liver injury. In mice, selective deletion of JNK1 and JNK2 in hepatocytes unexpectedly led to worsened liver injury, fibrosis, oxidative stress, and inflammatory signaling when animals were exposed to MASH-inducing diets. Mechanistically, the absence of hepatocyte JNK signaling resulted in marked activation of Caspase-8–dependent apoptosis, identifying Caspase-8 as a critical downstream effector driving hepatocyte death and fibrogenesis. Importantly, genetic or pharmacologic inhibition of Caspase-8 substantially improved liver injury and fibrosis, even in the setting of ongoing metabolic stress. Therapeutic silencing of Caspase-8 using lipid nanoparticle–delivered siRNA attenuated hepatocyte death and disease progression in vivo. Overall, this work reframes JNK signaling in MASH as a stress-adaptive, hepatoprotective pathway and identifies Caspase-8 as a promising, cell-specific therapeutic target. Rather than broadly inhibiting stress pathways, selectively blocking apoptosis downstream may offer a safer and more effective strategy for patients with MASH characterized by heightened oxidative stress.

Macrotrabecular HCC- Hepatology 26

Hepatocellular carcinoma (HCC) displays marked histologic heterogeneity that reflects distinct biological behaviors and treatment responses. Among recognized variants, macrotrabecular–massive HCC (MT-HCC) represents a particularly aggressive subtype characterized by thick tumor trabeculae wrapped by endothelial cells. A related vascular phenotype, vessels encapsulating tumor clusters (VETC), shares a similar “inverted” tumor–vessel architecture. Both patterns are strongly associated with early recurrence, metastasis, and poor prognosis. This commentary highlights emerging insights into the immunovascular biology underlying MT and VETC patterns. These tumors exhibit high expression of angiogenic factors such as VEGF-A and angiopoietin-2 and are frequently linked to oncogenic drivers including TP53 mutation, MYC activation, and Wnt/β-catenin signaling. The abnormal vasculature not only facilitates hematogenous spread but also contributes to an immunosuppressive microenvironment, marked by reduced T-cell infiltration and diminished interferon-γ–related signaling. Recent experimental work demonstrates that additional mediators, notably angiopoietin-like protein 2 (ANGPTL2) and IL-11, play key roles in shaping the macrotrabecular vascular pattern and suppressing antitumor immunity. Importantly, inhibiting angiogenic signaling—either genetically or pharmacologically—restores immune infiltration and enhances responsiveness to immune checkpoint blockade in preclinical models. Clinically, MT and VETC patterns can increasingly be inferred through imaging features, such as heterogeneous arterial enhancement, enabling noninvasive risk stratification. These findings support combined anti-angiogenic and immunotherapeutic strategies and underscore the need for integrated pathologic, radiologic, and immune profiling to guide personalised treatment in HCC.

A Whole-Blood Bioartificial Liver in Preclinical Models- J Hepatol Feb.26

Acute-on-chronic liver failure (ACLF) and acute liver failure (ALF) are life-threatening conditions marked by severe hepatic dysfunction combined with overwhelming systemic inflammation. Mortality remains extremely high because no available therapy can simultaneously control inflammation and replace lost liver function, leaving liver transplantation as the only definitive option for a limited number of patients. This study introduces UTOpiA, an integrated whole-blood extracorporeal bioartificial liver system designed to address both pathophysiologic drivers of liver failure. The system combines granulocyte–monocyte apheresis (GMA) to reduce systemic inflammation with human induced pluripotent stem cell–derived hepatocyte-like cell (iHLC) organoids engineered to lack key HLA molecules, minimising immune recognition. Importantly, the tandem design allows direct whole-blood perfusion, avoiding plasma separation and improving efficiency. In rat models of ACLF and ALF, a single UTOpiA treatment significantly improved survival compared with GMA alone, iHLCs alone, or earlier hepatoma-based devices. Treated animals showed reduced coma severity, improved liver biochemistry, lower ammonia and bilirubin levels, and marked suppression of inflammatory cytokines. Beyond metabolic support, UTOpiA also promoted liver regeneration: iHLC-derived α-fetoprotein enhanced hepatocyte cell cycling, while restoration of key hepatic transcription programs supported functional recovery. These findings demonstrate that integrating immunomodulation with hepatic metabolic and regenerative support can reverse severe liver failure in preclinical models. While clinical translation will require further validation, UTOpiA represents a major conceptual advance toward an off-the-shelf bioartificial liver therapy for patients with otherwise fatal liver failure.

Adipose Macrophage sEVs in MASH: Promise With Mechanistic Gaps- Gastroenterology Feb.26

Introduction Metabolically–dysfunction–associated steatohepatitis (MASH) is increasingly recognised as a multiorgan disease, with pathogenic signalling extending beyond the liver. Rohm et al. propose an intriguing extrahepatic mechanism: adipose tissue macrophage (ATM)–derived small extracellular vesicles (sEVs) carrying fibrogenic microRNAs (miR-155 and miR-34a) that activate hepatic stellate cells and promote liver fibrosis. This commentary welcomes the concept—but highlights important mechanistic and translational gaps that must be addressed before this pathway can be safely targeted in humans. Why this work matters Current antifibrotic strategies in MASH have largely focused on intrahepatic pathways. Demonstrating that adipose–liver communication via sEVs contributes to fibrosis would: expand therapeutic targets beyond the liver, explain why fibrosis can progress despite hepatic metabolic improvements, and open the door to novel interventions targeting immune–metabolic crosstalk. Key concerns and unresolved questions 1️⃣ Which macrophages are actually responsible? The study identifies expansion of CD9⁺ Trem2⁺ lipid-associated macrophages in adipose tissue. However: it does not distinguish resident ATMs from monocyte-derived infiltrating macrophages, nor does it clarify which subset produces fibrogenic sEVs. Why this matters clinically: Targeting “ATMs” broadly could disrupt beneficial immune or metabolic functions. Defining the exact macrophage subset is essential for selective and safer therapeutic strategies. 2️⃣ Why are miR-155 and miR-34a enriched in sEVs? The proposed mechanism assumes these miRNAs are selectively packaged into sEVs, but it remains unclear whether: they are simply overexpressed in donor macrophages, or actively sorted into vesicles via RNA-binding proteins. Why this matters: If miRNA enrichment is an active sorting process, it may be pharmacologically targetable. If passive, targeting upstream macrophage activation may be more effective than targeting sEVs themselves. 3️⃣ Is miRNA inhibition safe and durable? In vitro, antagomirs against miR-155 and miR-34a block stellate cell activation. However: miR-155 plays critical roles in immune regulation, miR-34a is involved in senescence and tumor suppression. Clinical concern: Systemic or long-term inhibition could lead to immunosuppression or oncogenic risk. Transient in vitro benefit does not guarantee sustained fibrosis regression or safety in vivo. 4️⃣ Macrophages are not static—how does polarisation matter? ATMs exist along a dynamic phenotypic spectrum, not fixed “pro-fibrotic” states. Changes in metabolic or inflammatory cues could: alter macrophage polarisation, reshape sEV cargo, and modify downstream fibrogenic signalling. Why this matters: Therapeutic strategies must account for macrophage plasticity, or risk short-lived or context-dependent efficacy. Translational interpretation This work represents an important conceptual advance—highlighting adipose tissue as an active driver of liver fibrosis in MASH via extracellular vesicles. However, before ATM-sEVs can be considered viable therapeutic targets, we need: clearer macrophage lineage tracing, mechanistic validation of miRNA sorting, long-term in vivo safety and efficacy data, and strategies that preserve beneficial immune–metabolic functions. Bottom-line takeaway for GastroAGI ATM-derived sEVs offer a compelling explanation for extrahepatic drivers of fibrosis in MASH—but therapeutic translation will require far more mechanistic precision and safety validation. One-line GastroAGI takeaway Adipose–liver communication via macrophage sEVs is a promising—but still incomplete—therapeutic frontier in MASH.

LKB1 Loss Primes the Serrated Pathway in the Intestine- Gastroenterology Feb.26

Introduction Peutz–Jeghers syndrome (PJS) is a hereditary cancer-predisposition condition caused by germline mutations in LKB1 (STK11). While patients are known to have an increased risk of gastrointestinal cancers, how partial loss of LKB1 reshapes intestinal epithelium to promote cancer has remained unclear. Traditionally, polyp formation in PJS has been attributed to non-epithelial mechanisms. This study challenges that view by showing that epithelial LKB1 loss alone is sufficient to reprogram intestinal cells into a premalignant state, closely resembling the serrated colorectal cancer pathway. The key problem Clinicians recognise serrated colorectal cancer as biologically distinct, often aggressive, and frequently associated with KRAS mutations and growth factor–driven signaling. What has been missing is a clear early molecular event that explains how epithelial tissue becomes “primed” for this pathway—particularly in hereditary cancer syndromes like PJS. What the authors did: Used CRISPR/Cas9 to create intestinal and colonic organoids with: one defective copy of LKB1 (heterozygous loss), and complete loss (loss of heterozygosity). Studied these models with: imaging, bulk and single-cell RNA sequencing, and growth factor dependency experiments. Validated findings in: human PJS intestinal tissue, and sporadic colorectal cancer datasets. Tested the interaction between LKB1 loss and KRAS mutations. Key findings clinicians should understand: 1) One “hit” is enough Loss of just one copy of LKB1 pushes intestinal epithelial cells into a premalignant transcriptional program. This program closely mirrors gene expression patterns seen in serrated colorectal cancer. 2) Loss of heterozygosity amplifies the effect When the remaining LKB1 allele is lost, the premalignant state is further intensified, strengthening the cancer-prone phenotype. 3) Chronic regeneration becomes the new normal LKB1-deficient cells show persistent features of tissue regeneration, rather than returning to a stable, differentiated state. This creates a biologically unstable environment favourable to neoplastic transformation. 4) EGFR signalling is central LKB1 loss leads to increased expression of EGFR ligands and receptors, allowing epithelial cells to grow independently of their normal niche signals—a classic hallmark of early cancer biology. 5) Synergy with KRAS explains serrated CRC risk When KRAS mutations were introduced, LKB1-deficient organoids showed synergistic growth and transcriptional changes, providing a mechanistic explanation for why LKB1 loss strongly aligns with the serrated cancer pathway. Why this matters clinically This work reframes PJS-associated cancer risk as an epithelial-intrinsic process, not merely a stromal or hamartomatous phenomenon. It provides a biological explanation for why LKB1 mutations are linked to serrated colorectal cancer, both hereditary and sporadic. It supports the concept that serrated carcinogenesis begins long before visible dysplasia, at the level of epithelial identity and growth control. It raises future possibilities for: early risk stratification, targeted surveillance, and pathway-based prevention strategies (e.g., EGFR-axis modulation). Bottom-line takeaway for GastroAGI Heterozygous LKB1 loss is not benign—it actively reprograms intestinal epithelium into a chronic regenerative, serrated cancer–prone state, long before overt malignancy appears. One-line GastroAGI takeaway LKB1 loss sets the molecular stage for serrated colorectal cancer.

Envbiotics-Front. Med. 2026

### What Are Envbiotics? Envbiotics is a term that encapsulates the idea of regulating and optimising gut microbiota indirectly by focusing on the environmental conditions of the gut rather than directly modifying microbial populations or supplying nutrients. Unlike prebiotics, which act as substrates for gut microbes, or postbiotics, which focus on metabolic by-products of microbes, Envbiotics emphasises non-nutritional factors that shape the gut microenvironment. These factors include: 1. **Physicochemical Conditions**: - Intestinal acidity - Oxidation-reduction potential - Osmotic balance - Temperature - Ion concentrations - Bile salts - Short-chain fatty acids 2. **Spatial Factors**: - The arrangement and integrity of the intestinal mucosal layer - The volume and composition of host mucus secretion 3. **Biological Markers**: - Levels of antimicrobial peptides - Immune cell functions - Presence of other symbiotic organisms ### Why Envbiotics Are Important The concept of Envbiotics addresses limitations in the current understanding of gut microbiota modulation. While prebiotics and postbiotics focus on nutrient-based or microbial by-product-based interventions, they often neglect the role of the gut's environmental conditions in shaping microbial behaviour. Envbiotics fills this gap by recognising that non-nutritional factors can profoundly influence the survival, colonisation, and function of gut microbes. ### Key Research Supporting Envbiotics 1. **Medications and Gut Microbiota**: Studies have shown that common medications, such as antidepressants, antipsychotics, and beta-blockers, can significantly alter gut microbiota by affecting the host's physiological state, even though these drugs are not directly metabolized by the microbes. 2. **Host-Microbe Interactions**: Host-derived factors such as mucin (e.g., MUC2) and proteins like FABP2 play critical roles in shaping microbial communities. For instance, disruptions in mucin production can lead to increased intestinal permeability and dysbiosis. 3. **Non-Nutritional Interventions**: - Acupuncture has been shown to regulate vagal activity, thereby influencing gut microbiota indirectly by modulating host immune status and digestive gland function. - Composite formulations like xyloglucan and pea protein have been reported to enhance intestinal barrier function and regulate microbiota homeostasis by forming a mechanical barrier in the mucosal layer. 4. **Biological Compounds**: - Pyrroloquinoline quinone (PQQ), a redox enzyme cofactor, selectively enriches beneficial bacteria by modulating the host's immune system and gut microenvironment, rather than acting directly on microbial populations. - Exosomes and vesicle-like components derived from plants or other sources influence gut microbiota indirectly by modulating host immune responses. ### Envbiotics as a Future Research Direction The concept of Envbiotics represents a paradigm shift in gut microbiota research and therapeutic approaches. By focusing on the environmental conditions critical for microbial survival and performance, Envbiotics offers a more holistic framework for understanding and optimizing host-microbe interactions. This approach could lead to: - Improved strategies for restoring gut microbiota balance in conditions like colitis, Crohn's disease, and dysbiosis. - Development of non-pharmaceutical interventions that enhance host health by optimizing the gut microenvironment. - A better understanding of how non-nutritional factors, such as stress, immune status, and external interventions, influence gut microbiota. ### Conclusion It highlights the importance of environmental modulation as a distinct pathway for regulating microbial communities and improving host health. If new developments in Envbiotics are published in 2026, they are likely to build on the foundational principles outlined here, offering deeper insights into the interplay between the gut microenvironment and microbiota.

What is serum Metabolomic Signature, Summary of the results (AP&T) - Jan,2026

It seems you're asking about the concept of serum metabolomic signatures and their summarized results as detailed in the study mentioned in the context. While the specific reference to "AP&T - Jan, 2026" appears to be a placeholder or a future event, I will summarize the findings from the provided context regarding serum metabolomic signatures and their importance in hepatocellular carcinoma (HCC): --- ### **What is a Serum Metabolomic Signature?** A serum metabolomic signature refers to a specific pattern of metabolites (small molecules) found in the blood. These patterns can provide insights into the biological processes occurring in the body, including those associated with diseases like cancer. In this context, serum metabolomic signatures were investigated as non-invasive biomarkers to predict tumor behavior and recurrence risk in patients with early-stage hepatocellular carcinoma (HCC). --- ### **Summary of the Results** 1. **High Recurrence Burden in HCC**: - Tumor recurrence is a common issue even after curative treatments for early-stage HCC, such as surgical resection or ablation. 2. **Need for Improved Risk Stratification**: - Current clinical models are insufficient in accurately predicting which patients are at higher risk of recurrence post-treatment. 3. **Serum Metabolomic Profiling**: - Comprehensive global metabolomic analysis was performed on serum samples collected from patients at diagnosis (before any treatment). This analysis identified circulating metabolites associated with tumor biology. 4. **Defined Metabolite Signatures**: - Two distinct metabolite signatures were identified, each reflecting different biological pathways: - **Signature 1**: Specifically associated with early tumor recurrence after treatment. - **Signature 2**: Associated with overall recurrence risk across the full follow-up period. 5. **Clinical Relevance of Signatures**: - These metabolite signatures were able to stratify patients into different risk groups for recurrence, providing a more tailored approach to post-treatment monitoring. 6. **Independence from Standard Clinical Factors**: - The predictive value of these metabolite signatures remained significant even after adjusting for traditional clinical and pathological variables. 7. **Link to Tumor Aggressiveness**: - The metabolite patterns appeared to reflect the underlying aggressiveness of the tumor biology. 8. **Validation in a US-Based Cohort**: - The study externally validated previously reported metabolite signatures in a cohort of US patients, confirming their reproducibility and reliability. 9. **Consistency Across Racial Groups**: - Performance of the metabolite signatures was consistent across major racial groups, indicating broad applicability. 10. **Aetiology-Specific Patterns**: - Differences in metabolite signatures were observed based on the underlying liver disease aetiology, suggesting that liver disease origin might influence metabolite profiles. 11. **No Clear Link to Overall Survival**: - While the signatures were predictive of recurrence risk, they did not show a direct association with overall mortality. 12. **Biological Plausibility**: - The identified metabolites align with known metabolic pathways implicated in HCC, supporting their relevance as biomarkers. 13. **Potential Clinical Utility**: - These serum metabolite signatures could be used to develop personalized surveillance and monitoring strategies for patients post-treatment, potentially improving outcomes by identifying high-risk individuals early. 14. **Scalability and Feasibility**: - As blood-based biomarkers, these signatures offer a practical and scalable approach for routine clinical use. 15. **Need for Larger Validation Studies**: - Although the findings are promising, further large-scale studies are needed to confirm the clinical utility of these metabolite signatures and establish their role in routine care. --- ### **Conclusion** Serum metabolomic signatures represent a promising non-invasive tool for risk stratification and monitoring in early-stage hepatocellular carcinoma. They provide insights into tumor aggressiveness and recurrence risk, independent of traditional clinical factors. If validated in larger studies, these biomarkers could pave the way for personalized post-treatment surveillance strategies, enhancing patient outcomes and optimizing resource allocation in clinical practice.

Cellular protagonists of Crohn’s fistula formation

The formation of fistulas in Crohn's disease (CD) involves specific cellular players and processes that contribute to their development and persistence. Recent research has revealed that fibroblasts, a type of connective tissue cell, play a central role in fistula formation. In fistulating CD patients, a unique group of fibroblasts, termed fistula-associated stromal (FAS) fibroblasts, was identified. These cells are linked to tissue remodeling, fibrosis (scar-like tissue formation), and immune modulation through cytokine production. Spatial mapping of fistula tracts showed that FAS fibroblasts organize in distinct layers. Closest to the fistula lumen is a proliferative zone rich in neutrophils and macrophages, surrounded by an active core of stromal fibroblasts. This is further encased by an outer quiescent zone of pro-fibrotic fibroblasts. These layers work together to sustain the fistula structure and promote its persistence. The study highlights that common molecular pathways and cellular environments drive fistula formation across different intestinal locations. While current treatments for CD mainly target inflammation, this research emphasizes the need to address the role of fibroblasts and their abnormal activity. By targeting these cellular mechanisms, new therapies could potentially reduce fistula formation and improve outcomes for CD patients.

The Protein Denitrosylase SCoR2 Regulates Lipogenesis and Fat Storage

Yes, the protein denitrosylase SCoR2 (SNO–CoA reductase 2) plays a central role in regulating lipogenesis (the process of lipid synthesis) and fat storage, as revealed in the research article. SCoR2 is proposed to act as a metabolic regulator, akin to sirtuins, but through controlling protein S-nitrosylation rather than acetylation. Here is a detailed explanation of how SCoR2 regulates lipogenesis and fat storage: ### 1. **Role in Adipose Tissue:** - **Promotion of Fat Storage:** SCoR2 promotes fat storage by denitrosylating the cytoskeletal regulator myosin 9 (Myh9). This denitrosylation suppresses actomyosin assembly, which is essential for enabling the activation of key lipogenic transcription factors. - **Activation of Lipogenic Transcription Factors:** These transcription factors include PPARγ, SREBP1, and CEBPα, which are vital for adipocyte differentiation and lipid synthesis. By activating these factors, SCoR2 drives the processes that lead to fat accumulation in adipose tissue. - **Impact of SCoR2 Loss or Inhibition:** When SCoR2 is lost or inhibited, the S-nitrosylation of Myh9 increases, disrupting the transcriptional programs required for lipogenesis. This limits the expansion of adipose tissue, effectively reducing fat storage. ### 2. **Role in the Liver:** - **Targeting Lipogenic Enzymes:** In the liver, SCoR2 directly targets enzymes involved in de novo lipogenesis, such as ATP citrate lyase (ACLY) and fatty acid synthase (FASN). These enzymes are critical for synthesizing lipids. - **Effect of Inhibition or Deletion:** When SCoR2 is inhibited or deleted, it increases the S-nitrosylation of ACLY and FASN, thereby reducing lipid synthesis. At the same time, this inhibition promotes fatty acid oxidation, which helps to break down fats. - **Protection Against Fat Accumulation:** This dual effect of reduced lipid synthesis and increased fat oxidation protects the liver from fat accumulation and injury, which are hallmarks of metabolic dysfunction–associated steatotic liver disease (MASLD). ### 3. **SCoR2 as a Therapeutic Target:** - The study identifies SCoR2 as a promising therapeutic target for obesity and MASLD. By targeting SCoR2, it may be possible to simultaneously limit lipid synthesis, enhance fat oxidation, and improve overall metabolic health. - This approach could address the root causes of excess lipid accumulation in adipose tissue and liver, which are central to the development of obesity and related metabolic disorders. ### Conclusion: SCoR2 regulates lipogenesis and fat storage through its denitrosylase activity, influencing key molecular pathways in both adipose tissue and liver. Its role as a metabolic regulator highlights its potential as a target for therapeutic strategies aimed at combating obesity, MASLD, and other lipid-related metabolic dysfunctions.

CTRB2 misfolding variant

The CTRB2 misfolding variant refers to a genetic alteration involving the deletion of exon 6 in the CTRB2 gene, which encodes a protein called chymotrypsinogen B2. This variant has been linked to an increased risk of pancreatic cancer due to its effects on protein folding and cellular stress. Research using a CRISPR/Cas9-engineered mouse model that mimics this human genetic variant has shown that the mutation causes the production of a truncated version of another related protein, CTRB1. This misfolded protein accumulates in the endoplasmic reticulum (ER), leading to ER stress and the formation of protein inclusions. The resulting ER stress disrupts normal pancreatic cell function, reducing chymotrypsin enzyme activity, protein synthesis, and secretion of digestive enzymes like amylase. Additionally, it activates inflammatory pathways and impairs the pancreas's ability to recover from injury, creating a pro-inflammatory and pro-cancer environment in the pancreas. This microenvironment increases the risk of developing pancreatic ductal adenocarcinoma (PDAC), a highly aggressive form of cancer. While this discovery highlights the potential of the CTRB2 variant as a marker for identifying individuals at higher risk of pancreatic cancer, routine genetic testing is not yet recommended. However, future strategies combining ER stress-relieving drugs and anti-inflammatory treatments may help mitigate this risk.

Oral microbiome and inflammatory bowel disease: New understanding and call to action

The relationship between the oral microbiome and inflammatory bowel disease (IBD) represents a rapidly evolving area of research that has expanded our understanding of IBD pathogenesis and progression. Traditionally, IBD was primarily associated with gut microbiome dysbiosis, but emerging evidence highlights the oral microbiome as a significant contributor, offering new insights into disease mechanisms and potential therapeutic strategies. This new understanding underscores the importance of integrating oral health into IBD care and calls for action to address this overlooked aspect of disease management. ### Key Insights into the Oral Microbiome and IBD: 1. **Oral Microbiome and Systemic Inflammation**: - The oral cavity is home to a diverse microbial ecosystem that plays critical roles in maintaining immune balance, digestion, and pathogen defense. When oral microbiota become dysbiotic, they can contribute to systemic inflammation by translocating microbes into circulation, activating immune responses, and releasing proinflammatory mediators. - Dysbiosis in the oral microbiome has been linked to gastrointestinal and systemic diseases, including IBD. This connection suggests that oral health is not isolated but intricately tied to gut health. 2. **Shared Microbial Signatures**: - In patients with Crohn’s disease and ulcerative colitis (the two primary forms of IBD), studies have identified shared microbial signatures between the oral cavity and the gut. During active disease, oral-associated bacteria are enriched in the gut, disrupting intestinal barrier integrity and amplifying inflammation. - Oral microbes can activate both innate and adaptive immune pathways, driving chronic inflammation through mechanisms such as cytokine signaling and oxidative stress. 3. **Periodontal Disease and IBD**: - Periodontal disease, a common oral inflammatory condition, is highlighted as both a potential contributor to and consequence of IBD. This bidirectional relationship reflects the interconnected nature of oral and gut inflammation. - Chronic periodontal inflammation may exacerbate IBD symptoms, while systemic inflammation from active IBD may worsen periodontal health. 4. **Metabolic Contributions**: - Oral bacteria influence metabolic processes by producing inflammatory metabolites and altering short-chain fatty acid dynamics. These changes can further aggravate intestinal inflammation and contribute to IBD progression. ### Diagnostic and Therapeutic Implications: 1. **Biomarkers for Disease Activity**: - Patterns in the oral microbiome may serve as biomarkers for IBD activity, offering new tools for diagnosis and disease monitoring. Identifying oral microbial signatures could help detect early signs of disease exacerbation. 2. **Targeting Oral Health in IBD Management**: - Improved dental hygiene, periodontal therapy, and oral probiotics are proposed as adjunctive strategies to manage IBD. These interventions aim to restore oral microbiome balance, reduce systemic inflammation, and potentially alleviate IBD symptoms. - Addressing oral health as part of IBD care may enhance treatment outcomes and support a more comprehensive approach to disease management. ### Call to Action: The emerging evidence calls for integrating oral health into IBD care, emphasizing the need for personalized, mechanism-driven treatment approaches that consider both oral and gut microbiomes. This paradigm shift requires collaboration between gastroenterologists, dentists, and microbiome researchers to: - Promote awareness of the oral–gut axis in IBD among healthcare providers. - Develop diagnostic tools that leverage oral microbial patterns as biomarkers. - Encourage patients with IBD to prioritize oral health through regular dental care and preventive measures. - Explore therapeutic interventions targeting oral dysbiosis as a novel avenue for managing IBD. In conclusion, the oral microbiome is a critical yet underappreciated factor in IBD pathogenesis and progression. Addressing oral health in IBD care has the potential to transform treatment strategies, offering a more holistic and effective approach to managing this chronic inflammatory condition.

Gut-lung immunometabolic crosstalk in sepsis

Gut-lung immunometabolic crosstalk in sepsis is a critical concept that highlights the bidirectional interactions between the gut and lungs, which play a pivotal role in the progression of sepsis and its associated complications, such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). This crosstalk is mediated by immune signaling, metabolites, and systemic circulation, creating a vicious cycle of immune-metabolic dysregulation that exacerbates inflammation, organ dysfunction, and respiratory failure. Below is a detailed explanation of the mechanisms and factors involved in gut-lung immunometabolic crosstalk during sepsis: ### 1. **Gut Microbiota Dysbiosis and Intestinal Barrier Dysfunction** - **Sepsis-induced microbiota dysbiosis:** Sepsis disrupts the gut microbiota composition, reducing beneficial microbes and increasing pathogenic species. This imbalance leads to the production of harmful metabolites and endotoxins, such as lipopolysaccharides (LPS). - **Intestinal barrier damage:** Sepsis compromises the intestinal epithelial barrier, allowing the translocation of endotoxins like LPS and microbial products into the systemic circulation. This leakage triggers systemic inflammation and immune activation, contributing to lung injury. ### 2. **Short-Chain Fatty Acids (SCFAs) and Gut Integrity** - SCFAs, produced by gut microbiota during fiber fermentation, play a crucial role in maintaining gut integrity and immune balance. In sepsis, reduced SCFA levels impair gut barrier function and exacerbate systemic inflammation, worsening the gut-lung axis imbalance. ### 3. **Inflammatory Amplification and Lung Injury** - **Endotoxin leakage:** LPS and other gut-derived toxins activate alveolar macrophages and neutrophils in the lungs, leading to excessive release of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α). This inflammatory cascade damages lung tissue and increases vascular permeability. - **Neutrophil extracellular traps (NETs):** Excessive NET formation in the lungs damages alveolar structures, impairs gas exchange, and increases the risk of respiratory failure. ### 4. **Metabolic Reprogramming in Immune Cells** - During early sepsis, immune cells undergo metabolic reprogramming, shifting from oxidative phosphorylation to glycolysis. This glycolytic shift, driven by hypoxia-inducible factor-1α (HIF-1α), fuels hyperinflammation and promotes the release of pro-inflammatory cytokines. - In later stages, mitochondrial dysfunction leads to energy exhaustion and immunosuppression, impairing the immune response and increasing susceptibility to secondary infections. ### 5. **Mitochondrial Dysfunction and Reactive Oxygen Species (ROS)** - Damaged mitochondria release reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), which act as damage-associated molecular patterns (DAMPs). These molecules amplify inflammation and contribute to multi-organ failure, including lung injury. ### 6. **Gut-Derived Metabolites and Lung Inflammation** - **Bile Acids and Tryptophan Metabolites:** Bile acids and tryptophan-derived metabolites, such as indole derivatives, regulate lung inflammation through nuclear receptors like FXR, TGR5, and AhR. Dysregulated levels of these metabolites in sepsis worsen lung injury. - **Succinate and TMAO Toxicity:** Accumulation of gut-derived metabolites like succinate and trimethylamine N-oxide (TMAO) enhances lung inflammation and pyroptosis, a form of programmed cell death. ### 7. **Macrophage Polarization Imbalance** - Gut dysbiosis skews macrophage polarization toward a pro-inflammatory M1 phenotype, while reducing the anti-inflammatory M2 phenotype. This imbalance worsens lung inflammation and contributes to ALI/ARDS. ### 8. **Vagus Nerve and Anti-inflammatory Pathway** - The vagus nerve connects the gut and lungs via the cholinergic anti-inflammatory pathway. Activation of α7 nicotinic acetylcholine receptors (α7nAChR) reduces cytokine release and protects lung tissues. Dysfunction of this pathway in sepsis exacerbates inflammation. ### 9. **Therapeutic Interventions** - **Probiotics and Prebiotics:** Probiotic therapy has shown potential in modulating gut microbiota and reducing inflammation. However, its use in ICU patients must be approached cautiously due to the risk of exacerbating sepsis. - **Fecal Microbiota Transplantation (FMT):** FMT can restore gut microbiota balance and reduce systemic inflammation in animal models. Human studies are limited but show promise. - **Precision Medicine:** Patient-specific immune-metabolic profiling is essential for tailoring therapies targeting the gut-lung axis. - **Multi-omics Approach:** Integrating metagenomics, metabolomics, and immunophenotyping can help identify dynamic biomarkers and develop targeted therapies. ### 10. **Clinical Vision** - Current sepsis management focuses on general immune suppression, but emerging research advocates for “immune-metabolic editing.” This approach aims to restore gut-lung axis balance, prevent organ failure, and improve outcomes by addressing the underlying immune-metabolic dysregulation. ### Conclusion Gut-lung immunometabolic crosstalk in sepsis is a complex interplay of disrupted gut microbiota, immune signaling, and metabolic dysfunction. Understanding and targeting this axis opens new avenues for precision medicine, with the potential to mitigate inflammation, prevent organ failure, and improve survival in sepsis patients.

Artesunate Induces Ferroptosis in Hepatic Stellate Cells and Alleviates Liver Fibrosis

Artesunate (Art) has emerged as a promising therapeutic agent for liver fibrosis due to its ability to induce ferroptosis in hepatic stellate cells (HSCs), which play a central role in the progression of liver fibrosis. Here is a detailed explanation of how Artesunate works and its potential therapeutic benefits: ### 1. **Hepatic Stellate Cells and Liver Fibrosis** - Liver fibrosis is a condition characterized by excessive deposition of extracellular matrix (ECM) proteins, primarily driven by the activation of HSCs. - Activated HSCs are responsible for producing fibrogenic proteins like α-SMA, Collagen I, and Fibronectin, which contribute to the scarring and progression of fibrosis. - Targeting HSCs to inhibit their activation or induce their death is a key strategy for combating liver fibrosis. ### 2. **Ferroptosis as an Anti-Fibrosis Strategy** - Ferroptosis is a regulated form of cell death characterized by iron overload, reactive oxygen species (ROS) accumulation, lipid peroxidation, and depletion of glutathione (GSH). - Inducing ferroptosis in activated HSCs offers a novel approach to reducing fibrogenic activity and alleviating liver fibrosis. ### 3. **Artesunate Induces Ferroptosis in HSCs** - Artesunate (Art), an anti-malarial drug, has been found to selectively induce ferroptosis in activated HSCs (e.g., LX2 cells) while sparing normal hepatocytes (LO2 cells) at therapeutic concentrations. - Mechanisms of ferroptosis induction by Art include: - Reduction of intracellular GSH levels. - Increase in free iron levels and lipid peroxidation (measured by malondialdehyde, MDA). - Elevation of ROS levels, as confirmed by DCFH-DA fluorescence assays. - These changes lead to ferroptotic death in HSCs, characterized by mitochondrial shrinkage, loss of cristae, and a shift in JC-1 fluorescence signals. ### 4. **Artesunate Suppresses HSC Activation** - Art downregulates key markers of HSC activation, including α-SMA, Collagen I, and Fibronectin, thereby reducing the fibrogenic potential of these cells. - This suppression of HSC activation further contributes to the alleviation of liver fibrosis. ### 5. **The ROCK1/ATF3 Axis: Key Regulatory Pathway** - Artesunate exerts its effects on HSCs through the ROCK1/ATF3 signaling axis: - Art promotes the degradation of ROCK1 (Rho-associated protein kinase 1) via the ubiquitin–proteasome pathway, while ROCK2 remains unaffected. - The reduction in ROCK1 levels decreases ATF3 phosphorylation, allowing ATF3 to accumulate in the nucleus. - Nuclear ATF3 suppresses the transcription of SLC7A11, a key component of the cystine/glutathione (GSH) pathway, leading to reduced cystine uptake and GSH depletion. - This cascade ultimately drives ferroptosis in HSCs. ### 6. **Key Experimental Findings** - **ATF3's Role:** ATF3 is essential for the induction of ferroptosis. Knockdown of ATF3 using siRNA reverses Art-induced ferroptosis, restores GSH levels, and reactivates HSCs. - **ROCK1's Role:** Overexpression of ROCK1 blocks the effects of Art, preventing ferroptosis, restoring mitochondrial function, and reversing the suppression of fibrogenic markers like α-SMA and Collagen I. - **Ferroptosis Inhibitors:** Agents like NAC (N-acetylcysteine, which increases intracellular GSH) and Fer-1 (a ferroptosis inhibitor) rescue HSCs from Art-induced ferroptosis, confirming the role of oxidative stress and lipid peroxidation in this process. ### 7. **In Vivo Evidence** - Artesunate has shown significant anti-fibrotic effects in animal models of liver fibrosis (e.g., CCl₄-induced mouse models): - Art reduces collagen deposition, improves hepatocyte architecture, and alleviates liver fibrosis. - Serum biomarkers of liver fibrosis, such as hyaluronic acid (HA), laminin (LN), procollagen III (PC-III), type IV collagen (IV-C), and liver enzymes (AST, ALT, ALP), improve significantly after Art treatment. - Targeting HSC-specific ATF3 or ROCK1 alters the outcomes of Art treatment in vivo. For example, ATF3 interference or ROCK1 overexpression diminishes Art's anti-fibrotic effects, further validating the importance of the ROCK1/ATF3 axis. ### 8. **Therapeutic Potential of Artesunate** - Artesunate's ability to selectively induce ferroptosis in activated HSCs while sparing normal hepatocytes makes it a highly promising candidate for anti-fibrosis therapy. - By targeting the ROCK1/ATF3 axis, Art effectively suppresses HSC activation, reduces fibrogenic protein production, and alleviates liver fibrosis in preclinical models. ### Conclusion: Artesunate represents a novel and effective therapeutic approach for liver fibrosis by inducing ferroptosis in activated HSCs through the ROCK1/ATF3 axis. Its ability to selectively target HSCs, coupled with strong preclinical evidence of efficacy, positions Artesunate as a potential anti-fibrotic agent for future clinical applications.

Integrated ubiquitomics characterization of hepatocellular carcinomas

The integrated ubiquitomics characterization of hepatocellular carcinomas (HCC) is a comprehensive study that combines proteomic, phosphoproteomic, and ubiquitomic analyses to uncover molecular mechanisms driving HCC progression and identify potential therapeutic targets. Below is a detailed overview based on the provided context: ### 1. **Comprehensive Multi-Omics Approach** The study utilized a multi-omics framework, integrating proteomics, phosphoproteomics, and ubiquitomics to analyze 85 HCC patient samples. This approach provided a detailed map of molecular alterations in HCC, revealing how protein modifications (e.g., phosphorylation and ubiquitination) influence tumor behavior. --- ### 2. **Key Findings and Insights** #### a. **Druggable Targets** - Two key therapeutic targets, **CBR1-S151** and **CPNE1-S55**, were identified as being overexpressed in HCC, particularly in aggressive forms of the disease. These targets hold promise for the development of novel treatments. #### b. **Prognostic Protein Markers** - Proteins such as **COL4A1**, **LAMC1**, and **LAMA4** were found to be highly expressed in patients with poor disease-free survival. These proteins are linked to extracellular matrix remodeling, which is associated with worse prognosis in HCC. #### c. **Tumor Pathway Cross Talk** - Phosphoproteomic and ubiquitomic analyses revealed significant overlap between metabolic and metastatic pathways. This cross-talk demonstrated how post-translational modifications like phosphorylation and ubiquitination drive HCC progression. #### d. **Subtype Classification** - Ubiquitomic profiling enabled the classification of HCC into molecular subtypes, distinguishing between aggressive and less aggressive tumor phenotypes. This stratification is crucial for personalized medicine and treatment planning. #### e. **Prognostic Biomarkers** - Differential ubiquitination of proteins such as **TUBA1A**, **BHMT2**, **BHMT**, and **ACY1** was strongly correlated with high prognostic risk scores. These biomarkers can be used to predict patient outcomes and guide clinical decision-making. --- ### 3. **Mechanistic Insights** #### a. **TUBA1A K370 Deubiquitination** - Deubiquitination of **TUBA1A** at lysine 370 (K370) was found to promote severe and aggressive HCC phenotypes. This modification stabilizes TUBA1A, enhancing its oncogenic effects. #### b. **AKT–USP14–TUBA1A Axis** - The study identified a crucial oncogenic pathway involving the **AKT-mediated activation of USP14**, which enhances TUBA1A deubiquitination. This stabilization of TUBA1A promotes tumor growth and progression in HCC. --- ### 4. **Therapeutic Implications** - Targeting the **AKT–USP14–TUBA1A complex** was shown to degrade TUBA1A and suppress liver tumorigenesis in vivo. This provides a novel therapeutic strategy for combating aggressive HCC. --- ### 5. **Clinical Relevance** - The study introduces a new ubiquitomic layer of tumor regulation in HCC, offering insights into biomarkers for diagnosis, prognosis, and treatment development. The findings have significant implications for improving patient stratification and tailoring therapeutic interventions. --- ### Conclusion The integrated ubiquitomics characterization of HCC has significantly advanced our understanding of the molecular mechanisms underlying tumor progression. By identifying key biomarkers, therapeutic targets, and oncogenic pathways, this study lays the foundation for the development of more effective diagnostic tools and personalized treatments for HCC.

unstable mitochondrial DNA mutations in HCC at single-cell resolution

Unstable mitochondrial DNA (mtDNA) mutations in hepatocellular carcinoma (HCC) were studied using a novel sequencing platform called single-cell capture-based mtDNA sequencing (sc-CAMS). This method allowed researchers to analyze mtDNA mutations at single-cell resolution, providing detailed insights into tumor heterogeneity. In the study, 1,641 single cells from 11 HCC patients and 528 cells from two xenograft mouse models were analyzed, revealing two types of mtDNA mutations: stable mutations (consistent heteroplasmy across cells) and unstable mutations (high variability in heteroplasmy among cells). Unstable mtDNA mutations were strongly linked to intratumor heterogeneity (ITH), a hallmark of aggressive tumors. Tumors with high levels of unstable mutations exhibited proliferative and aggressive clinical features. These mutations evolved bidirectionally during tumor progression, undergoing both positive selection (expansion) and negative selection (elimination), showcasing the dynamic nature of tumor evolution. Through evolutionary reconstruction, researchers demonstrated that HCC follows both linear and branched progression models, indicating multiple evolutionary paths within the same tumor. The study also visualized the spatiotemporal evolution of mtDNA mutations in patient-derived xenografts and multifocal tumor regions, showing how these mutations influence metabolic homeostasis, tumor evolution, and therapeutic resistance. Unstable mtDNA mutations could serve as biomarkers for tumor prognosis, stratification, and targeted therapies in HCC.

Role of TREM2 in Pancreatic Ductal Adenocarcinoma

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a receptor found on macrophages and other immune cells, playing a critical role in immune regulation and inflammation. In the context of Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive and treatment-resistant cancer, TREM2 has emerged as a key player in shaping the tumor microenvironment. The original study by Yang et al. demonstrated that TREM2 deficiency accelerates PDAC progression by promoting the infiltration of proinflammatory macrophages and enhancing IL-1β–mediated inflammation. This inflammatory cascade worsens the tumor’s immunosuppressive environment, allowing cancer cells to evade immune responses and proliferate more aggressively. Clinical biomarkers like soluble TREM2 (sTREM2) and IL-1β levels could help identify PDAC patients who might benefit from TREM2-targeted therapies. Spatial transcriptomics further offers insights into the spatial relationships between TREM2⁺ macrophages and IL-1β–rich regions, potentially correlating molecular profiles with patient survival outcomes or therapeutic responses. The gut and tumor microbiome also influence TREM2-driven inflammation, with microbial-derived metabolites such as short-chain fatty acids or lipopolysaccharides potentially modulating TREM2⁺ macrophage phenotypes. This highlights the interplay between microbial ecology and immune regulation in PDAC. Additionally, TREM2 interacts with other immune and stromal cells, such as cancer-associated fibroblasts (CAFs), T cells, and neutrophils, which collectively shape PDAC’s complex tumor microenvironment. Cytokines like IL-6 and TGF-β secreted by CAFs exacerbate IL-1β–driven inflammation, forming intricate feedback loops that worsen TREM2-deficient tumors. Future research aims to integrate multiomics approaches (transcriptomics, proteomics, microbiomics) to stratify patients molecularly and develop precision therapies targeting TREM2-related pathways. Understanding TREM2’s multidimensional role could pave the way for biomarker-driven, personalized strategies to combat PDAC effectively.

Elevated FBXO45 and metastatic HCC

Elevated FBXO45 expression has been identified as a critical driver of metastasis in hepatocellular carcinoma (HCC), particularly in cases involving TP53 mutations. Below is a detailed explanation of the relationship between elevated FBXO45 and metastatic HCC: ### 1. **FBXO45 Overview** FBXO45 is an E3 ubiquitin ligase that plays a central role in protein ubiquitination, a process that tags proteins for various cellular fates, including degradation or stabilization. In the context of HCC, FBXO45 has been shown to act as an oncogenic driver, promoting cancer progression and metastasis. ### 2. **FBXO45 Expression in TP53-Mutated HCC** - Elevated FBXO45 expression was observed in 78.3% of HCC patients with TP53 mutations, identifying an aggressive subtype of the disease. - TP53 mutations activate the mTOR signaling pathway, which in turn increases FBXO45 expression. This establishes a direct link between TP53 loss and the metastatic potential of HCC via the mTOR–FBXO45 axis. ### 3. **Pro-Metastatic Role of FBXO45** - **Enhanced Migration and Invasion:** FBXO45 overexpression significantly enhances the ability of HCC cells to migrate and invade, crucial steps in metastasis. Conversely, silencing FBXO45 suppresses these effects. - **Lung Metastases in Mice:** Experimental models demonstrated that FBXO45 overexpression led to a sevenfold increase in lung metastases, confirming its pro-metastatic role in vivo. - **EMT Induction:** FBXO45 promotes epithelial-to-mesenchymal transition (EMT), a process by which cancer cells acquire a more invasive and migratory phenotype. This is achieved by upregulating EMT markers such as N-cadherin, Snail, and vimentin, while downregulating E-cadherin. ### 4. **Mechanism of FBXO45-Driven Metastasis** FBXO45 drives HCC metastasis through a unique molecular mechanism involving the stabilization of the Trk-fused gene (TFG) protein: - **TFG Stabilization via Ubiquitination:** FBXO45 catalyzes K63-linked polyubiquitination at Lys103 (K103) of TFG. This noncanonical ubiquitination enhances TFG stability rather than targeting it for degradation. - **TFG's Role in Oncogenic Pathways:** Stabilized TFG interacts with activating transcription factor 2 (ATF2), which activates NF-κB signaling. NF-κB, in turn, promotes EMT and metastasis. ### 5. **Key Pathways Activated by FBXO45** - **ATF2–NF-κB Axis:** Stabilized TFG binds to ATF2, which upregulates NF-κB p65. This signaling cascade drives EMT and enhances the metastatic potential of HCC cells. - **mTOR Signaling:** TP53 mutations activate mTOR, which induces FBXO45 expression, linking TP53 loss to metastatic behavior through the mTOR–FBXO45–TFG axis. ### 6. **Clinical Implications** - **Correlation with Poor Prognosis:** High FBXO45 expression is positively correlated with TFG levels in clinical HCC samples (R = 0.52, p < 0.0001). Patients with co-overexpression of FBXO45 and TFG have significantly worse overall survival (p = 0.0015). - **Metastasis Confirmation in Humans:** Both FBXO45 and TFG are more highly expressed in HCC patients with distant metastases compared to non-metastatic cases. - **Independent of Proliferation:** Knockdown of TFG does not affect HCC cell proliferation but specifically inhibits FBXO45-induced migration and invasion, highlighting its metastasis-specific role. ### 7. **Therapeutic Potential** - **Targeting the Signaling Axis:** The TP53–FBXO45–TFG–ATF2–NF-κB axis represents a promising therapeutic target for aggressive, TP53-mutant HCC. - **Unique Mechanism of Action:** Unlike other E3 ubiquitin ligases, FBXO45 operates via the PAM–SKP1 complex instead of the typical Cullin1 scaffold, making it a distinct and potentially druggable target. ### 8. **Proposed Model of FBXO45-Driven Metastasis** The study proposes the following model: 1. TP53 mutations activate mTOR signaling. 2. mTOR signaling induces FBXO45 expression. 3. FBXO45 stabilizes TFG via K103-linked ubiquitination. 4. Stabilized TFG binds ATF2, activating NF-κB p65. 5. NF-κB signaling promotes EMT, driving HCC metastasis, particularly to the lungs. ### Conclusion Elevated FBXO45 expression is a key driver of metastasis in TP53-mutated HCC. By stabilizing TFG and activating the ATF2–NF-κB pathway, FBXO45 promotes EMT and enhances the metastatic potential of HCC cells. Its strong association with poor prognosis and its unique mechanism of action make FBXO45 a promising therapeutic target for aggressive HCC.

Mechanocrine signaling, Yap, HB-EGF, and liver regeneration.

Mechanocrine signaling, Yap (Yes-associated protein), HB-EGF (heparin-binding EGF-like growth factor), and liver regeneration are interconnected elements that play pivotal roles in the process of liver regrowth, particularly after partial hepatectomy (PHx). Below is a detailed explanation of their relationship and significance: ### **Mechanocrine Signaling in Liver Regeneration** Mechanocrine signaling refers to the process by which mechanical forces, such as shear stress and stretch, are converted into biochemical signals that drive cellular responses. In the context of liver regeneration: 1. **Triggering Events:** After PHx, the liver experiences increased sinusoidal blood flow and shear stress due to the reduced liver mass. These mechanical forces act as stimuli that initiate molecular and cellular responses independent of traditional ligand-receptor signaling. 2. **Key Players:** Liver sinusoidal endothelial cells (LSECs) are particularly responsive to these mechanical forces. They sense the increased flow and stretch, triggering intracellular signaling cascades. ### **Role of Yap in Mechanocrine Signaling** Yap is a transcriptional coactivator and a key mechanosensitive protein that translates mechanical signals into gene expression changes. Yap plays a critical role in liver regeneration by: 1. **Activation via Mechanical Stretch:** Increased sinusoidal flow activates integrin β1 on LSECs, leading to actin polymerization. This mechanical stretch facilitates Yap's migration into the nucleus. 2. **Nuclear Entry:** Actin polymerization opens nuclear pores, allowing Yap to enter the nucleus. 3. **Transcriptional Activation:** Once inside the nucleus, Yap forms a transcriptional complex with TEAD (TEA domain transcription factor). This complex drives the expression of genes involved in liver regeneration, including HB-EGF. ### **HB-EGF: A Key Mediator** HB-EGF is a growth factor that plays a dual role as both a signaling molecule and a bridge between endothelial cells and hepatocytes during liver regeneration: 1. **Induction by Mechanocrine Signaling:** The mechanical stretch of LSECs induces HB-EGF expression through the Yap-TEAD pathway. 2. **Timing:** HB-EGF levels begin to rise within 3 hours after PHx and peak at around 48 hours, coinciding with the peak of hepatocyte proliferation. 3. **Action on Hepatocytes:** HB-EGF secreted by LSECs binds to EGFR (epidermal growth factor receptor) on hepatocytes, promoting their proliferation and contributing to the restoration of liver mass. ### **Mechanistic Cascade** The sequence of events following PHx and the role of mechanocrine signaling can be summarized as follows: 1. **Mechanical Trigger:** Increased sinusoidal flow and shear stress activate integrin β1 on LSECs. 2. **Actin Polymerization:** Integrin β1 signaling induces actin polymerization, opening nuclear pores. 3. **Yap Activation:** Yap migrates to the nucleus and binds TEAD to initiate transcriptional programs. 4. **HB-EGF Expression:** Yap-TEAD drives the upregulation of HB-EGF in LSECs. 5. **Endothelial-Hepatocyte Communication:** HB-EGF acts on hepatocytes via EGFR, promoting their proliferation. ### **Cooperation with Other Signals** While mechanocrine signaling is crucial, liver regeneration also depends on classical ligand-receptor signaling pathways: 1. **EGFR and MET Activation:** Growth factors like EGF, TGFα, HB-EGF, and HGF activate receptor tyrosine kinases (EGFR and MET), driving hepatocyte proliferation. 2. **Extracellular Matrix Remodeling:** Early activation of urokinase releases active HGF from the extracellular matrix, further enhancing mitogenic signaling alongside HB-EGF. ### **Significance of Yap and Mechanocrine Signaling** 1. **Essential Role:** Inhibition of Yap, either genetically or pharmacologically, suppresses HB-EGF expression, confirming that Yap is indispensable for this mechanocrine pathway. 2. **Flow-Dependent Regulation:** The amount of HB-EGF produced by LSECs is directly proportional to the mechanical stress they experience, emphasizing the importance of blood flow in driving liver regeneration. 3. **New Paradigm:** Mechanocrine signaling via Yap and HB-EGF represents a novel and underappreciated mechanism in liver regeneration biology. It complements classical signaling pathways, highlighting the liver's ability to integrate mechanical and biochemical cues. ### **Parallel Mechanosensitive Pathways in Hepatocytes** Similar mechanosensitive mechanisms are likely active in hepatocytes themselves: 1. **Integrin β1 and Yap Activation:** Mechanical stress may also activate integrin β1 and Yap in hepatocytes, promoting their proliferation. 2. **Early Activation Events:** Rapid membrane potential changes, β-catenin, and Notch-1 activation in hepatocytes suggest an immediate mechanochemical response following PHx. ### **Conclusion** Mechanocrine signaling, mediated by Yap and HB-EGF, is a crucial component of liver regeneration. It highlights the liver's unique ability to use mechanical forces, alongside classical ligand-receptor interactions, to coordinate the complex process of tissue regrowth. This paradigm emphasizes the integration of mechanical and biochemical signals in organ regeneration, providing new insights into liver biology and potential therapeutic targets for liver injuries or diseases.

Stretch-induced hepatic endothelial mechanocrine and hepatocyte proliferation

The study focuses on how mechanical stretching of liver sinusoidal endothelial cells (LSECs) after partial hepatectomy (surgical removal of a part of the liver) triggers liver regeneration by promoting hepatocyte (liver cell) proliferation. When part of the liver is removed, blood flow per unit of liver volume increases, causing the liver's tiny blood vessels (sinusoids) to stretch. This stretch acts as a signal for regeneration. A key finding was the role of a protein called HB-EGF (heparin-binding EGF-like growth factor), which is crucial for hepatocyte proliferation. The mechanical stretch of LSECs causes them to produce HB-EGF through a process called "mechanotransduction," where physical forces are converted into biochemical signals. This process depends on YAP (Yes-associated protein), which moves into the cell nucleus and activates genes like *Hbegf* that promote HB-EGF production. YAP's nuclear entry happens via two mechanisms: 1) passive entry through expanded nuclear pores due to F-actin polymerization, and 2) active transport assisted by a protein called BAG3. β1-integrin, a receptor on LSECs, acts as the key mechanosensor that detects the stretch and starts this signaling cascade. The HB-EGF secreted by stretched LSECs activates EGFR signaling in hepatocytes, stimulating their proliferation and aiding liver recovery. This "mechanocrine" process—mechanical forces triggering biochemical signals—links blood flow changes to liver regeneration, highlighting a novel pathway for understanding liver repair.

STARD1 promotes cholestatic liver injury and disease progression

Yes, STARD1 (Steroidogenic Acute Regulatory Protein D1) plays a key role in promoting cholestatic liver injury and disease progression. Cholestatic liver diseases occur when bile acids, which are made from cholesterol, build up in the liver cells (hepatocytes). This buildup causes liver damage, inflammation, scarring (fibrosis), and can eventually lead to cirrhosis. STARD1 is a protein that helps transport cholesterol into mitochondria, where it can be used to make bile acids through a specific pathway. However, too much mitochondrial cholesterol, facilitated by STARD1, disrupts the liver’s natural defenses against oxidative stress. This makes the liver more vulnerable to damage from toxic bile acids. Studies in mice have shown that removing STARD1 specifically from liver cells (Stard1^Δhep^ mice) protects them from cholestatic injury. These mice had lower levels of harmful bile acids and mitochondrial cholesterol, less oxidative stress, and better antioxidant defenses, particularly higher levels of mitochondrial glutathione (mGSH). As a result, they experienced less liver inflammation and fibrosis compared to normal mice. In humans, patients with primary biliary cholangitis (PBC), a type of cholestatic liver disease, show higher levels of STARD1 in their liver, linking it to disease severity. Targeting STARD1 or its effects on mitochondrial cholesterol and glutathione metabolism could be a promising treatment strategy for cholestatic liver diseases.

Intestinal Gas and its role in SIBO

Intestinal gas plays a significant role in both normal gastrointestinal function and in pathological conditions such as Small Intestinal Bacterial Overgrowth (SIBO). To fully understand its implications in SIBO, it is important to first explore the nature of intestinal gas, its composition, and how it is affected by SIBO. ### **What is Intestinal Gas?** Intestinal gas is a byproduct of digestion and fermentation processes in the gastrointestinal tract. It is composed of various gases including: 1. **Hydrogen (H₂)**: Produced during carbohydrate fermentation by gut bacteria. 2. **Methane (CH₄)**: Generated by methanogenic archaea in the gut. 3. **Carbon dioxide (CO₂)**: Released during fermentation and chemical reactions in the gut. 4. **Nitrogen (N₂) and Oxygen (O₂)**: Derived from swallowed air. 5. **Hydrogen sulfide (H₂S)**: Produced during the breakdown of sulfur-containing compounds. 6. **Trace gases**: Includes ammonia and volatile organic compounds. In normal individuals, the production and release of these gases are balanced, and most of the gases are either absorbed into the bloodstream or expelled through the rectum. ### **Role of Intestinal Gas in Normal Physiology** - **Digestion**: Intestinal gas is a natural byproduct of the fermentation of undigested carbohydrates, fibers, and resistant starches by gut bacteria. - **Microbial Activity**: Gas production reflects the activity of gut microbiota, which play a crucial role in breaking down complex carbohydrates and producing short-chain fatty acids (SCFAs) that nourish intestinal cells. - **Motility**: Intestinal gas can stimulate motility by stretching the intestinal walls, promoting the movement of food and waste through the digestive tract. ### **Intestinal Gas in SIBO** SIBO is a condition characterized by an abnormal overgrowth of bacteria in the small intestine, where bacterial populations are typically lower compared to the colon. This excessive bacterial presence disrupts the normal balance and function of the gut, leading to altered gas production and associated symptoms. #### **Gas Production in SIBO** 1. **Excess Hydrogen (H₂)**: - SIBO often involves excessive fermentation of carbohydrates in the small intestine, leading to increased hydrogen production. - Hydrogen gas is produced by bacteria when they metabolize fermentable carbohydrates. - This excess hydrogen can contribute to symptoms such as bloating, abdominal pain, and diarrhea. 2. **Methane (CH₄)**: - In some cases of SIBO, methanogenic archaea (e.g., *Methanobrevibacter smithii*) utilize hydrogen to produce methane. - Methane gas is associated with constipation-predominant symptoms, as it slows intestinal motility. 3. **Hydrogen sulfide (H₂S)**: - Certain bacteria in SIBO may produce hydrogen sulfide, which can irritate the intestinal lining and contribute to symptoms such as diarrhea and abdominal discomfort. 4. **Carbon dioxide (CO₂)**: - Increased bacterial activity in the small intestine may also lead to elevated production of carbon dioxide, contributing to bloating and distension. #### **Symptoms of Intestinal Gas in SIBO** The abnormal gas production in SIBO leads to a range of gastrointestinal symptoms: - **Bloating and distension**: Excess gas causes visible abdominal swelling and discomfort. - **Diarrhea or constipation**: Depending on the type of gas (hydrogen or methane), SIBO can cause either diarrhea or constipation. - **Flatulence**: Increased gas production often results in excessive passing of gas. - **Abdominal pain**: Gas buildup can stretch the intestinal walls, leading to cramping or pain. #### **Role of Diet in Gas Composition in SIBO** The types of gas produced in SIBO are heavily influenced by dietary choices: - **High-carbohydrate diets**: Promote fermentation and hydrogen production, exacerbating symptoms. - **High-fiber diets**: May worsen bloating and gas production in individuals with SIBO, as fiber is fermented by gut bacteria. - **FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols)**: These fermentable carbohydrates are poorly absorbed and can significantly increase gas production in SIBO. #### **Diagnosis of SIBO Using Gas** Breath tests are commonly used to diagnose SIBO. These tests measure the levels of hydrogen and methane in the breath after consuming a sugar solution (e.g., glucose or lactulose). Elevated levels of hydrogen or methane suggest bacterial overgrowth in the small intestine. #### **Management of Intestinal Gas in SIBO** 1. **Antibiotics**: - Rifaximin is commonly used to target hydrogen-producing bacteria. - If methane production is predominant, a combination of rifaximin and neomycin may be prescribed to target methanogenic archaea. 2. **Dietary Modifications**: - Low-FODMAP diet: Reducing fermentable carbohydrates can help minimize gas production and alleviate symptoms. - Specific Carbohydrate Diet (SCD): Focuses on easily digestible carbohydrates to reduce fermentation. 3. **Probiotics**: - Certain probiotics may help restore a healthy balance of gut bacteria, though their use in SIBO is controversial and requires careful selection. 4. **Motility Agents**: - Drugs like prokinetics may be used to improve gut motility and reduce the risk of bacterial overgrowth. ### **Conclusion** Intestinal gas is a normal byproduct of digestion, but its production becomes excessive and symptomatic in conditions like SIBO. The type and volume of gas produced depend on the bacterial composition of the gut and dietary habits. In SIBO, excessive hydrogen, methane, and other gases can significantly impair gut function, leading to symptoms such as bloating, abdominal pain, diarrhea, or constipation. Proper diagnosis and targeted treatment, including antibiotics, dietary changes, and motility support, are essential for managing intestinal gas and alleviating the discomfort associated with SIBO.

Pancreatic Acinus and Pancreatic Stellate Cells

Pancreatic Acinus and Pancreatic Stellate Cells are important components of the pancreas, which is a gland located in the abdomen. Here's a detailed explanation of both: ### **Pancreatic Acinus:** 1. **Definition:** Pancreatic acini are small clusters of cells in the pancreas responsible for producing and secreting digestive enzymes. These enzymes help in breaking down food in the small intestine. 2. **Structure:** Acini are made up of acinar cells, which are pyramid-shaped cells. These cells surround a small central duct, forming a grape-like structure. The central duct drains the enzymes produced by acinar cells. 3. **Function:** - Acinar cells synthesize and secrete enzymes such as amylase (for carbohydrate digestion), lipase (for fat digestion), and proteases (for protein digestion). - These enzymes are released into the pancreatic ducts and eventually reach the small intestine to aid digestion. - Acinar cells also produce inactive enzyme precursors (zymogens) to prevent damage to the pancreas itself. These precursors become active in the intestine. 4. **Regulation:** Hormones like **cholecystokinin (CCK)** and **secretin** regulate the activity of acinar cells. CCK stimulates enzyme secretion, while secretin promotes the release of bicarbonate to neutralize stomach acid. --- ### **Pancreatic Stellate Cells (PSCs):** 1. **Definition:** Pancreatic stellate cells are specialized cells located in the pancreas that play a role in maintaining the organ's structure and responding to injury or inflammation. 2. **Structure:** These cells have a star-shaped appearance (hence the name "stellate"). They are found in the connective tissue around the acini and ducts. 3. **Function:** - **Normal State:** In a healthy pancreas, PSCs are inactive and help maintain the extracellular matrix (the supporting structure of the pancreas). - **Activated State:** When the pancreas is injured or inflamed (e.g., in pancreatitis or pancreatic cancer), PSCs become activated. In this state, they produce collagen and other substances that lead to fibrosis (scarring). - PSCs are involved in repairing damage but excessive activation can lead to fibrosis, which disrupts normal pancreatic function. 4. **Role in Disease:** - In chronic pancreatitis and pancreatic cancer, PSCs contribute to the development of fibrosis, making these conditions worse. - They are a focus of research for developing therapies to prevent or reduce fibrosis in pancreatic diseases. --- ### **Key Differences Between Pancreatic Acinus and Stellate Cells:** | **Feature** | **Pancreatic Acinus** | **Pancreatic Stellate Cells** | |-------------------------------|--------------------------------------------|---------------------------------------------| | **Location** | Found in clusters (acini) around ducts | Found in connective tissue around acini | | **Function** | Produces digestive enzymes | Maintains extracellular matrix, responds to injury | | **Role in Disease** | Dysfunction leads to reduced enzyme production (e.g., exocrine insufficiency) | Excessive activation leads to fibrosis in pancreatic diseases | --- ### **Clinical Significance:** 1. **Pancreatic Acinus:** Dysfunction in acinar cells can lead to conditions like exocrine pancreatic insufficiency, where the pancreas fails to produce enough digestive enzymes. This results in malabsorption and digestive problems. 2. **Pancreatic Stellate Cells:** Overactivation of PSCs is linked to chronic pancreatitis and pancreatic cancer. Research is ongoing to find ways to inhibit PSC activation and reduce fibrosis. Understanding the roles of these cells is crucial for diagnosing and treating pancreatic diseases effectively.

The Mesentery and Its Role in Gastroenterology

The mesentery is a vital structure within the human body, playing an essential role in the gastrointestinal (GI) system. Once thought to be a fragmented and insignificant structure, recent advancements in anatomical and clinical research have redefined the mesentery as a **continuous organ** with critical functions in maintaining GI health and contributing to disease pathology. Below is an in-depth exploration of the mesentery and its role in gastroenterology: --- ### **1. What is the Mesentery?** The mesentery is a **double-layered fold of the peritoneum** that anchors the intestines to the posterior abdominal wall. It serves as a **conduit for blood vessels, lymphatics, and nerves**, ensuring the intestines receive the necessary support for digestion, absorption, and immune defense. It is now recognized as a **distinct organ** due to its unique anatomical and functional properties. #### **Structure and Anatomy**: - The mesentery is composed of **two layers of peritoneum** that enclose: - Blood vessels (arteries and veins). - Lymphatic vessels and lymph nodes. - Nerve fibers (autonomic and enteric nervous systems). - Connective tissue and adipose tissue. - It is classified into different regions based on the part of the GI tract it supports: 1. **Mesentery Proper**: Suspends the small intestine (jejunum and ileum). 2. **Transverse Mesocolon**: Supports the transverse colon. 3. **Sigmoid Mesocolon**: Anchors the sigmoid colon. 4. **Mesoappendix**: Connects the appendix. 5. **Mesorectum**: Surrounds the rectum and is critical in rectal cancer surgeries. #### **Embryological Development**: - The mesentery develops from the **dorsal mesentery** during embryogenesis, which suspends the primitive gut tube. - The **ventral mesentery** persists only in the foregut and forms structures like the falciform ligament and lesser omentum. --- ### **2. Functions of the Mesentery** The mesentery performs several essential functions that are critical for gastrointestinal health and overall homeostasis: #### **a. Structural Support**: - The mesentery anchors the intestines to the abdominal wall, ensuring their proper positioning within the abdominal cavity. - It provides flexibility and mobility for the intestines, which is essential for digestion, peristalsis, and the passage of food. #### **b. Vascular Supply**: - The mesentery contains the **arteries and veins** that supply the intestines: - **Arteries**: The superior mesenteric artery (SMA) and inferior mesenteric artery (IMA) deliver oxygenated blood and nutrients to the intestines. - **Veins**: Drain deoxygenated blood into the portal venous system for processing in the liver. - Disruption to this vascular supply can lead to severe conditions like **mesenteric ischemia**. #### **c. Lymphatic Drainage**: - The mesentery contains an extensive network of **lymphatic vessels and lymph nodes** that: - Drain lymph from the intestines. - Play a key role in immune surveillance and the filtration of pathogens. - Absorb dietary fats and fat-soluble vitamins via specialized lymphatic vessels called **lacteals**. #### **d. Immune Defense**: - The mesentery harbors immune cells (macrophages, lymphocytes, dendritic cells) that regulate gut immunity. - **Mesenteric lymph nodes** are central to immune responses, balancing tolerance to commensal gut bacteria and defense against pathogens. - It also modulates inflammation, playing a role in conditions like **Crohn’s disease** and **mesenteric panniculitis**. #### **e. Fat Storage**: - The mesentery contains adipose tissue, which serves as an energy reserve. - However, excessive fat deposition (mesenteric obesity) is associated with metabolic syndrome and inflammatory conditions, such as **Crohn’s disease**. #### **f. Nervous System Integration**: - The mesentery contains nerve fibers that are part of the **enteric nervous system (ENS)**. - These nerves regulate intestinal motility, secretion, and blood flow, which are essential for digestion and nutrient absorption. --- ### **3. The Mesentery in Gastrointestinal Diseases** The mesentery plays a significant role in the pathogenesis and management of various gastrointestinal conditions. These include: #### **a. Mesenteric Ischemia**: - A condition caused by reduced blood flow to the intestines due to occlusion or narrowing of mesenteric arteries. - **Acute Mesenteric Ischemia (AMI)**: A life-threatening emergency caused by embolism or thrombosis in the superior mesenteric artery. Symptoms include severe abdominal pain, nausea, and vomiting. Prompt diagnosis and revascularization are critical. - **Chronic Mesenteric Ischemia (CMI)**: Caused by atherosclerosis, leading to postprandial abdominal pain and weight loss. Treatment involves angioplasty, stenting, or surgical bypass. #### **b. Mesenteric Lymphadenitis**: - Inflammation of mesenteric lymph nodes, often due to infections like **viral gastroenteritis** or **Yersinia enterocolitica**. - Symptoms include abdominal pain, fever, and nausea, often mimicking appendicitis. - Management involves supportive care and antibiotics if a bacterial infection is present. #### **c. Mesenteric Panniculitis**: - A rare inflammatory condition involving the mesenteric fat, characterized by inflammation, fat necrosis, and fibrosis. - Symptoms include abdominal pain, bloating, diarrhea, and weight loss. - Diagnosis is often made through imaging, which shows a "misty mesentery" appearance. - Treatment may involve corticosteroids or immunosuppressive medications. #### **d. Crohn’s Disease**: - In Crohn’s disease, the mesentery plays a significant role in disease progression. - **Creeping Fat**: Mesenteric fat expands and wraps around inflamed bowel segments, contributing to chronic inflammation, fibrosis, and strictures. - Surgical resection of the mesentery along with the affected bowel is often necessary to reduce disease recurrence. #### **e. Mesenteric Tumors**: - **Primary Mesenteric Tumors**: Rare tumors such as mesenteric fibromatosis and liposarcomas. - **Secondary Tumors**: The mesentery is a common site for metastases from gastrointestinal cancers, such as colorectal and gastric cancer. #### **f. Superior Mesenteric Artery Syndrome (SMAS)**: - A rare condition caused by compression of the duodenum between the superior mesenteric artery and the aorta, often due to rapid weight loss. - Symptoms include postprandial pain, nausea, and vomiting. - Management involves nutritional support or surgical intervention. #### **g. Mesenteric Cysts**: - Fluid-filled cysts that can be congenital or acquired, often asymptomatic but may cause abdominal pain or obstruction. - Treatment involves surgical excision. --- ### **4. Clinical Importance of the Mesentery** #### **a. Recognition as an Organ**: - The mesentery is now considered a **distinct organ**, emphasizing its critical role in the body’s anatomy and physiology. - This recognition has spurred new research into the mesentery’s involvement in health and disease. #### **b. Surgical Relevance**: - The mesentery is central to modern surgical techniques, particularly in colorectal cancer and inflammatory bowel disease (IBD). - **Total Mesorectal Excision (TME)** is the gold standard for rectal cancer, involving precise removal of the mesorectum to prevent recurrence. #### **c. Role in Immunity**: - The mesentery is a key player in gut immunity, regulating the balance between tolerance to beneficial gut microbes and defense against harmful pathogens. - Dysregulated immune responses in the mesentery contribute to inflammatory diseases like Crohn’s disease and mesenteric panniculitis. #### **d. Vascular and Lymphatic Importance**: - The mesenteric vasculature is prone to life-threatening ischemic conditions that require prompt diagnosis and treatment. - The mesentery also acts as a pathway for the spread of cancer and other diseases through its lymphatic network. --- ### **5. Future Perspectives** The growing understanding of the mesentery as an organ has opened new avenues for research and clinical applications. Areas of interest include: - **Targeted therapies** for inflammatory and neoplastic diseases involving the mesentery. - **Immunological studies** to understand the mesentery’s role in gut homeostasis and immune regulation. - **Surgical advancements** to improve outcomes in procedures like colorectal cancer surgery and Crohn’s disease management. --- ### **Conclusion** The mesentery is more than just a passive structural support for the intestines. It is a dynamic organ that plays a central role in gastrointestinal health, vascular and immune functions, and disease processes. Its recognition as an independent organ has revolutionized our understanding of its importance in gastroenterology, paving the way for new diagnostic and therapeutic approaches. By continuing to explore the mesentery’s functions and its role in various diseases, researchers and clinicians can improve patient outcomes and develop innovative treatments for complex GI conditions.

Intraepithelial Lymphocytes (IELs) and Their Role in Gastrointestinal (GI) Conditions

**Intraepithelial Lymphocytes (IELs) and Their Role in Gastrointestinal (GI) Conditions** Intraepithelial lymphocytes (IELs) are a specialized subset of immune cells that reside within the epithelial lining of the gastrointestinal (GI) tract. They are strategically positioned to serve as the first line of defense against pathogens while simultaneously maintaining tolerance to harmless commensal microorganisms and dietary antigens. Dysregulation of IELs is implicated in several GI disorders, including celiac disease, inflammatory bowel disease (IBD), and gastrointestinal malignancies. Below, we delve into the details of IELs, their characteristics, functions, and their involvement in various GI conditions. --- ### **1. Overview of IELs** #### **Definition and Location**: - IELs are specialized T lymphocytes located between epithelial cells of the intestinal mucosa. - They are predominantly found in the **small intestine** and **colon**, where they make up a significant proportion of mucosal immune cells. #### **Types of IELs**: IELs are categorized based on the type of T-cell receptors (TCRs) they express: 1. **TCR-αβ IELs**: - Derived from the thymus. - Express conventional T-cell markers (CD4+ or CD8+). - Recognize antigens presented by major histocompatibility complex (MHC) molecules. - Participate in adaptive immune responses. 2. **TCR-γδ IELs**: - Develop independently of the thymus. - Do not require antigen presentation by MHC molecules. - Play a role in innate-like immune responses and epithelial repair. - Found in higher proportions in the small intestine compared to the colon. #### **Functions of IELs**: - **Immune Surveillance**: IELs monitor the epithelial barrier and respond rapidly to invading pathogens by releasing cytokines and cytotoxic granules (e.g., perforin and granzymes). - **Epithelial Barrier Maintenance**: TCR-γδ IELs secrete growth factors, such as keratinocyte growth factor (KGF), which aid in epithelial repair. - **Regulation of Inflammation**: IELs maintain immune tolerance to commensal bacteria and dietary antigens, preventing excessive inflammation. - **Cytotoxicity**: CD8+ TCR-αβ IELs directly kill infected or transformed epithelial cells by recognizing antigens presented by MHC class I molecules. --- ### **2. Role of IELs in GI Conditions** #### **a. Celiac Disease (CeD)**: Celiac disease is one of the most studied conditions associated with IELs. - **Pathophysiology**: - In celiac disease, gluten peptides (e.g., gliadin) are presented by antigen-presenting cells (APCs) in the context of HLA-DQ2 or HLA-DQ8 molecules to CD4+ T cells, initiating an inflammatory response. - This leads to recruitment and activation of **CD8+ TCR-αβ IELs**, which damage epithelial cells by releasing cytotoxic molecules (e.g., perforin and granzyme) and pro-inflammatory cytokines (e.g., IFN-γ, TNF-α). - TCR-γδ IELs also increase in number and contribute to epithelial damage and inflammation. - Histologically, celiac disease is characterized by **villous atrophy**, **crypt hyperplasia**, and **increased IELs** (≥25 IELs/100 epithelial cells). - **Clinical Relevance**: - **IEL count** is a critical diagnostic criterion for celiac disease. Increased IELs are used in the Marsh classification system (Marsh 1–3). - Persistent elevation of IELs despite a gluten-free diet may indicate **refractory celiac disease (RCD)** or progression to **enteropathy-associated T-cell lymphoma (EATL)**. --- #### **b. Refractory Celiac Disease (RCD)**: - **RCD Type I**: - Retains a polyclonal T-cell population of IELs. - Represents a less severe form of the disease, often responsive to immunosuppressive therapy. - **RCD Type II**: - Characterized by clonal expansion of aberrant IELs that lack surface CD3 but express intracellular CD3 and CD8. - Associated with a high risk of progression to **enteropathy-associated T-cell lymphoma (EATL)**. --- #### **c. Enteropathy-Associated T-Cell Lymphoma (EATL)**: - EATL is a rare, aggressive T-cell lymphoma arising from malignant transformation of IELs, typically in patients with long-standing or untreated celiac disease. - **Pathogenesis**: - Chronic inflammation due to gluten exposure leads to genetic mutations in IELs, resulting in monoclonal proliferation and lymphoma. - Individuals with HLA-DQ2 or HLA-DQ8 haplotypes are at higher risk. - **Clinical Presentation**: - Symptoms include abdominal pain, weight loss, diarrhea, and complications like small bowel perforation or obstruction. - **Diagnosis**: - Biopsy reveals sheets of atypical lymphocytes, often accompanied by necrosis and ulceration. - Immunophenotyping shows CD3+CD8+ T cells with high proliferative activity. - **Prognosis**: - Poor, with a median survival of less than one year due to the aggressive nature of the disease. --- #### **d. Inflammatory Bowel Disease (IBD)**: - **Role of IELs**: - In **Crohn’s disease** and **ulcerative colitis**, IEL numbers and activity are dysregulated. - Dysregulated IELs contribute to mucosal inflammation, epithelial damage, and impaired barrier function. - **Paneth Cell Dysfunction**: - Paneth cells play a key role in antimicrobial defense. In Crohn’s disease, their dysfunction is linked to abnormal IEL activity, increasing susceptibility to microbial invasion. - **Clinical Implications**: - Persistent inflammation driven by dysregulated IELs can lead to complications such as strictures, fistulas, and an increased risk of colorectal cancer. --- #### **e. Infectious Enteritis**: - During infections (e.g., viral, bacterial, or parasitic), IELs play a vital role in controlling pathogens by: - Releasing **pro-inflammatory cytokines** (e.g., IFN-γ, TNF-α). - Directly killing infected epithelial cells via cytotoxic mechanisms. - Excessive activation of IELs can lead to tissue damage and chronic inflammation. --- #### **f. HIV-Associated Enteropathy**: - In HIV infection, **CD4+ T cells**, including CD4+ IELs, are significantly depleted, impairing mucosal immunity. - This results in chronic immune activation, microbial translocation, and gut barrier dysfunction, which are hallmarks of HIV-associated enteropathy. --- #### **g. Graft-versus-Host Disease (GVHD)**: - In hematopoietic stem cell transplantation, donor-derived T cells target the recipient’s GI epithelial cells, leading to severe inflammation. - IELs play a dual role: - They exacerbate epithelial damage by releasing pro-inflammatory cytokines. - They also regulate inflammation and promote epithelial repair in certain contexts. --- ### **3. Clinical Assessment of IELs** #### **Histological Evaluation**: - IELs are counted in intestinal biopsy samples, typically from the duodenum or small intestine. - **Normal IEL count**: **<25 per 100 epithelial cells**. - Increased IELs are a hallmark of conditions like celiac disease, IBD, and infections. #### **Immunophenotyping**: - Flow cytometry and immunohistochemistry are used to characterize IEL subsets (e.g., TCR-αβ, TCR-γδ, CD4+, CD8+). --- ### **Summary of IELs in GI Conditions** | **Condition** | **Role of IELs** | **Clinical Relevance** | |----------------------------------|----------------------------------------------------------------------------------|---------------------------------------------------------------------------------------| | **Celiac Disease** | Increased IELs due to immune response to gluten peptides | Diagnostic marker (≥25 IELs/100 epithelial cells in duodenal biopsy). | | **Refractory Celiac Disease** | Clonal expansion of aberrant IELs (Type II) | Increased risk of progression to enteropathy-associated T-cell lymphoma (EATL). | | **Enteropathy-Associated T-Cell Lymphoma (EATL)** | Malignant transformation of IELs due to chronic inflammation | Aggressive malignancy with poor prognosis. | | **Inflammatory Bowel Disease** | Dysregulated IEL activation contributes to chronic inflammation in Crohn’s/UC | May lead to epithelial damage, dysbiosis, and complications like fistulas or strictures. | | **Infectious Enteritis** | Activation of IELs to fight pathogens | Excessive activation may cause tissue damage and chronic inflammation. | | **HIV-Associated Enteropathy** | Depletion of CD4+ IELs leads to impaired mucosal immunity | Increased risk of microbial translocation and chronic immune activation. | | **Graft-versus-Host Disease** | Donor-derived T cells target recipient’s epithelial cells | IELs contribute to epithelial damage and inflammation. | --- ### **Take-Home Points** 1. **IELs** are critical immune cells within the epithelial lining of the GI tract, serving as the first line of defense. 2. They are involved in **immune surveillance**, **epithelial repair**, and **regulation of inflammation**. 3. Dysregulation of IEL activity is a hallmark of GI conditions such as **celiac disease**, **IBD**, **infectious enteritis**, and **HIV-associated enteropathy**. 4. Persistent activation or clonal expansion of IELs can lead to severe complications, such as **refractory celiac disease** or **EATL**. 5. Clinical evaluation of IELs through **biopsy** and **immunophenotyping** is essential for diagnosing and managing GI diseases. Understanding the role of IELs is key to developing targeted therapies and improving outcomes for patients with GI disorders.

Goblet Cells and Peneth Cells in Gastroenterology

### Goblet Cells and Paneth Cells in Gastroenterology: An In-Depth Overview Goblet cells and Paneth cells are specialized epithelial cells that are essential for maintaining the health and functionality of the gastrointestinal (GI) tract. They play crucial roles in gut homeostasis, immune defense, digestion, and protection against pathogens. Their dysfunction is associated with several gastrointestinal disorders, making them a key focus in gastroenterology research and clinical practice. --- ### **Goblet Cells** #### **1. Location and Morphology**: - Goblet cells are dispersed throughout the epithelial lining of the gastrointestinal tract, as well as the respiratory and reproductive tracts. - In the GI tract, they are most abundant in the **small intestine** and **colon**, with their highest density found in the distal colon. - **Morphology**: - Goblet cells have a characteristic cup-like shape. - The apical region contains mucin granules, giving the cell a swollen appearance. - The basal region houses the nucleus and organelles. #### **2. Functions**: - **Mucus Secretion**: - Goblet cells secrete **mucins**, which are glycoproteins that form mucus upon hydration. - Mucus acts as a protective barrier, shielding the intestinal lining from mechanical damage, digestive enzymes, and pathogens. - **Immune Function**: - Goblet cells release **mucosal immunoglobulins (IgA)** and antimicrobial peptides, which are critical components of the innate immune defense. - They also assist in delivering antigens to immune cells in the gut-associated lymphoid tissue (GALT), modulating immune responses. - **Lubrication**: - Mucus facilitates the smooth passage of food and fecal matter through the GI tract, reducing friction. #### **3. Clinical Relevance**: - **Inflammatory Bowel Disease (IBD)**: - Goblet cell dysfunction is central to diseases like **ulcerative colitis (UC)** and **Crohn’s disease**. - A reduction in goblet cell numbers and impaired mucus production leads to a compromised protective barrier, increasing susceptibility to bacterial invasion, inflammation, and tissue damage. - **Colorectal Cancer (CRC)**: - Goblet cell differentiation is often lost in colorectal cancer, resulting in reduced mucin secretion. This compromises the mucosal barrier and promotes tumorigenesis. - **Infections**: - A dysfunctional mucus barrier increases vulnerability to infections, as pathogens can more easily invade the intestinal lining. --- ### **Paneth Cells** #### **1. Location and Morphology**: - Paneth cells are specialized secretory cells found at the **base of the crypts of Lieberkühn** in the small intestine, primarily in the **ileum**. They are rare in the large intestine. - **Morphology**: - Paneth cells are pyramid-shaped and contain large eosinophilic granules filled with antimicrobial peptides. #### **2. Functions**: - **Innate Immunity**: - Paneth cells secrete antimicrobial peptides, including **defensins**, **lysozymes**, and **phospholipase A2**, which protect the intestinal mucosa by killing pathogenic bacteria. - **Stem Cell Niche Maintenance**: - Paneth cells support intestinal stem cells located in the crypts by secreting growth factors such as **Wnt**, **Notch ligands**, and **epidermal growth factor (EGF)**. These factors are crucial for the continuous renewal of the intestinal epithelium. - **Regulation of Microbiota**: - Through the secretion of antimicrobial peptides, Paneth cells help maintain a balanced gut microbiota and prevent bacterial overgrowth. #### **3. Clinical Relevance**: - **Inflammatory Bowel Disease (IBD)**: - Paneth cell dysfunction, particularly impaired antimicrobial peptide secretion, is strongly associated with **Crohn’s disease**, especially in cases involving the ileum. This can lead to dysbiosis and increased susceptibility to infections. - **Necrotizing Enterocolitis (NEC)**: - In premature infants, immature Paneth cells and insufficient defensin production are linked to NEC, a severe inflammatory condition of the intestine. - **Cancer**: - Altered Paneth cell function and disrupted stem cell signaling can lead to intestinal tumorigenesis. - **Paneth Cell Metaplasia**: - Paneth cells, normally restricted to the small intestine, can appear in the colon in response to chronic inflammation, as seen in **ulcerative colitis** and **chronic infections**. --- ### **Comparison of Goblet Cells and Paneth Cells** | **Feature** | **Goblet Cells** | **Paneth Cells** | |----------------------------|--------------------------------------------|------------------------------------------| | **Location** | Found throughout the GI tract, most abundant in the colon | Found at the crypt base of the small intestine (especially the ileum) | | **Primary Function** | Secretion of mucins for mucus production | Secretion of antimicrobial peptides | | **Role in Immunity** | Secrete IgA and modulate immune response | Innate immunity via antimicrobial peptides (e.g., defensins) | | **Role in Gut Homeostasis**| Protects mucosal surface and facilitates lubrication | Maintains gut microbiota and supports stem cell niche | | **Response to Inflammation** | Decrease in number and function in IBD | Dysfunction in Crohn's disease, Paneth cell metaplasia in UC | | **Histological Appearance**| Cup-shaped with apical mucin granules | Pyramid-shaped with eosinophilic granules | --- ### **Clinical Implications in Gastroenterology** 1. **Inflammatory Bowel Disease (IBD)**: - Both goblet and Paneth cells are pivotal in IBD pathogenesis. - **Goblet cell dysfunction** leads to a thinner mucus layer, increasing bacterial invasion and inflammation. - **Paneth cell dysfunction** exacerbates dysbiosis and inflammation, especially in Crohn’s disease. 2. **Colorectal Cancer (CRC)**: - Loss of goblet cell differentiation and reduced mucin secretion are early events in colorectal cancer development. - Paneth cell dysfunction can alter stem cell niche signaling, promoting tumor growth. 3. **Infectious Diseases**: - Impaired goblet and Paneth cell functions heighten susceptibility to infections such as **Clostridium difficile** and other enteric pathogens. 4. **Necrotizing Enterocolitis (NEC)**: - Immature Paneth cells in preterm infants contribute to NEC, highlighting the importance of antimicrobial peptides in neonatal gut protection. 5. **Cystic Fibrosis**: - Goblet cells often become hyperplastic in cystic fibrosis, leading to excessive mucus production and intestinal obstruction. 6. **Celiac Disease**: - Reduced goblet cell numbers and altered Paneth cell function due to chronic inflammation may impair mucosal protection in celiac disease. --- ### **Conclusion** Goblet cells and Paneth cells are integral to the structure and function of the gastrointestinal tract. Their roles in mucus secretion, immune defense, and maintaining gut homeostasis are critical for preventing disease and ensuring normal digestion. Dysfunction in these cells has profound implications for gastrointestinal health, contributing to inflammatory, infectious, and neoplastic conditions. Understanding their biology and clinical significance is essential for advancing diagnostics and therapeutic strategies in gastroenterology.

MOGAT2 influence colorectal cancer progression through ACSM1-mediated lipid metabolic reprogramming

Monoacylglycerol O-acyltransferase 2 (MOGAT2) plays a significant role in influencing colorectal cancer (CRC) progression by regulating lipid metabolism through ACSM1 (Acyl-CoA synthetase medium-chain family member 1). In a study investigating MOGAT2’s role, researchers found that its expression directly impacts tumor behavior. When MOGAT2 was suppressed, CRC cells exhibited aggressive characteristics, including increased proliferation, invasion, and colony formation, along with reduced apoptosis (cell death). These changes suggest a more malignant cancer phenotype. On the other hand, overexpressing MOGAT2 reversed these effects, reducing tumor growth and invasion, promoting apoptosis, and inhibiting epithelial-mesenchymal transition (EMT), a process critical for cancer metastasis. Mechanistically, MOGAT2 reprograms lipid metabolism in CRC cells. It reduces the accumulation of free fatty acids, regulates cholesterol transport, and suppresses the expression of lipid synthesis enzymes like GPAT2, GPAT3, and GAAT. This reprogramming helps restore metabolic balance in cancer cells, which is crucial for controlling their growth and spread. Further analysis identified ACSM1 as a key downstream mediator of MOGAT2’s tumor-suppressive effects. ACSM1 contributes to the metabolic changes induced by MOGAT2. When ACSM1 was silenced, the beneficial effects of MOGAT2 overexpression were lost, and cancer cells regained aggressive traits, reduced apoptosis, and experienced metabolic dysregulation. In summary, MOGAT2 acts as a tumor suppressor in CRC by modulating lipid metabolism through ACSM1. This pathway reduces tumor growth, promotes apoptosis, and inhibits invasion and EMT. Targeting the MOGAT2–ACSM1 axis may offer a promising therapeutic approach for managing CRC progression.

miR147 promotes mucosal integrity and intestinal inflammation

miR147 plays a crucial role in promoting mucosal integrity and regulating intestinal inflammation. As a protective microRNA, miR147 is specifically enriched in intestinal epithelial cells (IECs), particularly in differentiated enterocytes at the luminal surface of the colon. Its expression is intrinsic to epithelial differentiation and not dependent on microbial exposure, as demonstrated in germ-free mice. During inflammation, miR147 expression is upregulated in response to cytokine-driven signals, as observed in dextran sodium sulfate (DSS)-induced colitis models and inflammatory conditioned media experiments. Functionally, miR147 is vital for maintaining epithelial barrier integrity and promoting mucosal healing during inflammation. Global and epithelial-specific miR147 knockout mice exhibit severe colitis characterized by significant body weight loss, shortened colons, epithelial destruction, and increased intestinal permeability. Transcriptomic analysis revealed that miR147 suppresses proinflammatory and mitochondrial metabolism genes, particularly Ndufa4, a mitochondrial complex IV-associated gene. Ndufa4 was identified as a direct target of miR147, and its dysregulation in miR147-deficient tissues leads to disrupted metabolism and weakened barrier function. Mechanistic studies confirmed that the miR147–Ndufa4 axis is essential for epithelial homeostasis, as mice engineered to lack the miR147 binding site in Ndufa4 mirrored the severe inflammation seen in miR147 knockouts. Furthermore, miR147 supports robust type I interferon signaling in colonocytes, enhancing antiviral and anti-inflammatory defense while sustaining metabolic balance. The study suggests that miR147 mimics or Ndufa4-targeted therapies could restore mucosal healing and reduce inflammation, highlighting miR147 as a potential therapeutic target for inflammatory bowel disease (IBD) and colorectal cancer.

Salvigenin Inhibits Gastric Cancer Progression via EGFR/PI3K/AKT-Mediated Antitumor Signaling

Yes, salvigenin inhibits gastric cancer progression by targeting the EGFR/PI3K/AKT signaling pathway, which plays a critical role in tumor growth, survival, and aggressiveness. The study highlights the following key findings: 1. **Anticancer Properties of Salvigenin**: Salvigenin, a bioactive flavonoid, demonstrated significant anticancer effects in gastric cancer cells. It reduced cell proliferation, migration, and invasion while promoting apoptosis, effectively curbing the malignancy of gastric cancer. 2. **Mechanism of Action**: Mechanistic investigations using network pharmacology, molecular docking, and protein expression analyses revealed that salvigenin exerts its antitumor effects primarily by inhibiting the EGFR/PI3K/AKT signaling pathway. This pathway is well-known for its role in promoting tumor cell survival, proliferation, and metastasis. 3. **Validation of Mechanism**: - **Rescue Experiments**: When EGFR signaling was artificially activated using NSC 228155 or EGFR overexpression, the inhibitory effects of salvigenin on cancer cell malignancy were reversed. This strongly supports the conclusion that salvigenin's anticancer effects are mediated through the suppression of EGFR/PI3K/AKT signaling. - **In Vivo Evidence**: In xenograft mouse models, salvigenin effectively suppressed tumor growth, confirming its ability to block the EGFR/PI3K/AKT pathway and reduce tumor progression in a living organism. 4. **Therapeutic Potential**: Salvigenin's ability to target a key oncogenic pathway (EGFR/PI3K/AKT) positions it as a promising candidate for targeted therapy in gastric cancer management. By reducing tumor aggressiveness and enhancing apoptosis, salvigenin offers a potential approach for improving outcomes in gastric cancer patients. In summary, salvigenin's inhibition of the EGFR/PI3K/AKT signaling pathway is central to its anticancer effects, making it a potent agent for combating gastric cancer progression.

Interferon-gamma in driving crypt hyperplasia in celiac disease

Interferon-gamma plays a crucial role in driving crypt hyperplasia, a hallmark of celiac disease and other inflammatory intestinal disorders. Crypt hyperplasia refers to the abnormal elongation and proliferation of epithelial crypts in the intestinal lining, which is commonly observed in active celiac disease. Research using mass spectrometry-based tissue proteomics revealed strong interferon-gamma activity in the epithelial crypt zone of patients with active celiac disease. This was evidenced by increased expression of major histocompatibility complex (MHC) molecules and decreased levels of proteins involved in fatty acid metabolism, indicating significant molecular changes in the intestinal epithelium. To further investigate, experiments in wild-type mice demonstrated that administration of interferon-gamma reproduced the morphological and molecular features of crypt hyperplasia, confirming its role in driving this pathological process. Importantly, mice lacking interferon-gamma receptors specifically in gut epithelial cells did not develop crypt hyperplasia when exposed to interferon-gamma, providing direct evidence that interferon-gamma acts on epithelial cells to induce these changes. Overall, interferon-gamma is a direct driver of crypt hyperplasia in celiac disease, highlighting its critical role in the disease's pathogenesis. It may also play a similar role in other inflammatory intestinal disorders involving interferon-gamma signaling, making it a potential therapeutic target for these conditions.

Hesperetin, Liver Fibrosis, Gut Microbiota and Autophagy

Hesperetin, a naturally occurring flavonoid with notable anti-inflammatory and antioxidant properties, has shown promising effects in addressing liver fibrosis, a condition characterized by excessive scarring due to chronic liver injury. In a mouse model of carbon tetrachloride-induced liver fibrosis, hesperetin demonstrated significant antifibrotic potential. It reduced liver injury and fibrosis, improved liver tissue structure, and suppressed autophagy-related markers in hepatic stellate cells, which are key drivers of fibrosis. By inhibiting the activation of these cells, hesperetin effectively limited the progression of fibrosis and decreased inflammatory cell infiltration within the liver. Additionally, hesperetin influenced gut microbiota composition, an important factor in liver health. Using 16S rDNA sequencing, researchers observed that hesperetin increased the proportion of Firmicutes and boosted beneficial populations of lactic acid bacteria. These changes in gut microbial balance contributed to reduced liver inflammation and fibrosis, highlighting the gut-liver axis's role in disease modulation. The study concluded that hesperetin alleviates liver fibrosis through a multifaceted mechanism involving the suppression of hepatic stellate cell autophagy, reduction of inflammation, and restoration of healthy gut microbiota. These findings suggest hesperetin as a potential therapeutic candidate for managing liver fibrosis and improving overall liver health.

Hypoxia-Activated CAFs Promote Lymphatic Metastasis in Colorectal Cancer via CLEC11A/LGR5-Mediated WNT Signaling.

The title "Hypoxia-Activated CAFs Promote Lymphatic Metastasis in Colorectal Cancer via CLEC11A/LGR5-Mediated WNT Signaling" succinctly encapsulates the findings of the study. Here's an in-depth explanation of the key points: 1. **Hypoxia and Cancer-Associated Fibroblasts (CAFs):** - Hypoxia, a condition of low oxygen levels in the tumor microenvironment, plays a significant role in cancer progression and metastasis. - Under hypoxic conditions, normal fibroblasts are converted into cancer-associated fibroblasts (CAFs) by the activation of the transcription factor HIF1A (Hypoxia-Inducible Factor 1-alpha). - These hypoxia-activated CAFs exhibit altered behavior, including increased secretion of specific proteins that influence tumor progression. 2. **CLEC11A Secretion by Hypoxic CAFs:** - Hypoxic CAFs were found to secrete CLEC11A, a protein that plays a pivotal role in promoting cancer metastasis. - CLEC11A binds to the LGR5 receptor, which is present on colorectal cancer cells. 3. **CLEC11A/LGR5 Interaction and WNT Signaling:** - The interaction between CLEC11A and LGR5 activates the WNT/beta-catenin signaling pathway, a well-known pathway involved in cancer progression. - Activation of this pathway drives epithelial-mesenchymal transition (EMT), a process where cancer cells lose their epithelial characteristics and gain mesenchymal traits, making them more invasive and motile. - The WNT signaling pathway also promotes lymphangiogenesis, the formation of new lymphatic vessels, which facilitates the spread of cancer cells through the lymphatic system. 4. **Lymphatic Metastasis:** - The combined effects of EMT and lymphangiogenesis significantly enhance the ability of colorectal cancer cells to metastasize via the lymphatic system, contributing to disease progression and poor prognosis. 5. **Therapeutic Insights:** - Inhibiting CLEC11A secretion from CAFs was shown to significantly reduce lymphatic metastasis in both cell and animal models. - Blocking the LGR5 receptor or interfering with the WNT signaling pathway also reversed the metastatic effects, highlighting the therapeutic potential of targeting the CLEC11A-LGR5 axis. - These findings suggest that strategies aimed at disrupting this signaling axis could serve as effective treatments to prevent cancer spread in colorectal cancer patients. 6. **Clinical Implications:** - The study provides a deeper understanding of how the tumor microenvironment, specifically hypoxia and CAF activity, drives lymphatic metastasis in colorectal cancer. - Targeting the hypoxia-induced CLEC11A/LGR5-mediated WNT signaling pathway could offer a novel therapeutic approach to combat colorectal cancer metastasis and improve patient outcomes. In summary, the research underscores the critical role of hypoxia-activated CAFs in promoting lymphatic metastasis in colorectal cancer through the CLEC11A/LGR5-mediated activation of the WNT signaling pathway. This discovery not only elucidates a key mechanism of cancer progression but also identifies potential targets for therapeutic intervention.

Impact of HMOX1 + Macrophages on Tumor Immunity and Immunotherapy Response in HCC

HMOX1-positive (HMOX1+) macrophages have a profound impact on tumor immunity and the response to immunotherapy in hepatocellular carcinoma (HCC), as revealed by the study. Here is a detailed explanation of their role: ### 1. **HMOX1+ Macrophages and Tumor Immunity:** - **Immunosuppressive Role:** HMOX1+ macrophages are tumor-associated macrophages (TAMs) that play a central role in creating an immunosuppressive tumor microenvironment (TME). These macrophages are characterized by the high expression of heme oxygenase 1 (HMOX1), an enzyme involved in heme metabolism and cellular stress responses. - **Immune Cell Infiltration:** Tumors with elevated levels of HMOX1+ macrophages show increased infiltration of regulatory T cells (Tregs). Tregs are known to suppress anti-tumor immune responses, further contributing to immune evasion by the tumor. - **CD8+ T Cell Dysfunction:** In the presence of HMOX1+ macrophages, CD8+ T cells exhibit elevated expression of programmed cell death protein 1 (PD-1), a marker of T cell exhaustion. Exhausted CD8+ T cells are less effective in recognizing and killing cancer cells, which undermines the anti-tumor immune response. ### 2. **Impact on Immunotherapy Response:** - **Poor Prognosis and Reduced Responsiveness:** The study found that the presence of HMOX1+ macrophages in the TME is associated with poorer prognosis in HCC patients. Additionally, these macrophages correlate with reduced responsiveness to immunotherapy, particularly immune checkpoint inhibitors like anti-PD-1 therapy. - **Immune Resistance:** HMOX1+ macrophages contribute to an immune-resistant environment by promoting Treg infiltration and CD8+ T cell exhaustion, making the tumor less susceptible to immunotherapy. ### 3. **Therapeutic Implications – Targeting HMOX1:** - **Pharmacological Inhibition of HMOX1:** The study demonstrated that inhibiting HMOX1 pharmacologically using Znpp (Zinc protoporphyrin IX) improved the efficacy of anti-PD-1 therapy in preclinical mouse models of HCC. This suggests that targeting HMOX1+ macrophages can reverse the immunosuppressive state of the TME. - **Enhanced Immunotherapy Effectiveness:** By reducing the activity of HMOX1, the study observed improved anti-tumor immune responses, likely due to decreased Treg infiltration and reduced PD-1 expression on CD8+ T cells. This indicates that HMOX1 inhibition reactivates exhausted T cells and restores their ability to fight the tumor. ### 4. **Prognostic and Therapeutic Potential of HMOX1:** - **Prognostic Marker:** The expression of HMOX1 in tumor-associated macrophages could serve as a biomarker for predicting patient prognosis and their likely response to immunotherapy. - **Combination Therapy:** Combining HMOX1 inhibitors with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 therapies) could provide a synergistic effect, enhancing the overall success of immunotherapy in HCC patients. ### Conclusion: HMOX1+ macrophages play a critical role in promoting an immunosuppressive TME in HCC, leading to poor prognosis and reduced effectiveness of immunotherapy. Targeting HMOX1, either alone or in combination with existing immunotherapies, represents a promising strategy to overcome immune resistance and improve clinical outcomes for HCC patients. This approach could potentially transform the treatment landscape for this highly challenging cancer.

Lipid Metabolism Signature in NAFLD Revealed by Transcriptomic and Single-Cell RNA-Seq Analyses

The study identified key lipid metabolism-related genes (LMGs) associated with nonalcoholic fatty liver disease (NAFLD) using transcriptomic and single-cell RNA sequencing (scRNA-seq) analyses. Researchers analyzed multiple datasets (GSE48452, GSE63067, GSE89632, GSE72756) alongside scRNA-seq data (GSE159977). They identified 295 differentially expressed genes (DEGs) between NAFLD and controls, with 24 LMGs linked to fatty acid metabolism, bile acid metabolism, and inflammation. NAFLD patients were classified into two clusters based on these LMGs. Cluster 1 showed inhibited fatty acid metabolism but activated inflammatory and TNF signaling pathways, indicating disease heterogeneity. Using machine learning methods (LASSO, BSR, Boruta), three key LMGs—PRKAA2, KLF5, and ME1—were identified. ME1 and PRKAA2 were validated as core genes for diagnostic modeling, with ME1 showing stronger biological relevance. A two-gene diagnostic model integrating PRKAA2 and ME1 achieved high accuracy (AUC = 0.945). Immune analysis revealed significant associations of ME1 and PRKAA2 with immune cells, especially NK and T cells, highlighting immune-metabolic crosstalk in NAFLD. scRNA-seq identified six cell types, with NK cells strongly correlating with ME1 expression. NAFLD samples showed reduced T-cell proportions but elevated NK-cell infiltration, indicating immune imbalance. ME1 was found to drive lipid accumulation and influence NK-cell metabolic activity, while PRKAA2's role was context-dependent. Functional pathway analysis revealed that differential LMGs were involved in TNF, JAK–STAT, AMPK, and PPAR signaling, which regulate lipid metabolism and inflammation. The study underscores ME1’s potential as a biomarker and therapeutic target, linking lipid dysregulation and immune imbalance in NAFLD. Future studies should validate these findings and explore ME1’s therapeutic potential.

Lactylation-based gene signature and gastric adenocarcinoma

Gastric adenocarcinoma (STAD) is a type of stomach cancer that accounts for 95% of gastric cancers and has poor survival rates. A recent study focused on a biological process called "lactylation," where lactate molecules attach to proteins, influencing metabolism and gene expression in cancer. The study aimed to identify lactylation-related genes (LRGs) that could predict patient outcomes and immune system involvement in STAD. Researchers analyzed data from 375 STAD samples and 32 normal tissues, identifying 12 key LRGs. They built a six-gene model (including DHRS7, NOP2, CRABP2, CALD1, ALB, and RIMS1) to predict patient survival. Patients with higher risk scores had shorter survival times. Among these genes, DHRS7 was studied in-depth. DHRS7 levels were lower in cancer tissues but higher in advanced stages, correlating with worse outcomes. It was linked to immune cells like macrophages, particularly M2 macrophages, which promote an immunosuppressive tumor environment. DHRS7 also influenced key cancer pathways (e.g., PI3K-AKT and TGF-β) and processes like tumor growth, invasion, and immune escape. Interestingly, DHRS7 acted as a tumor suppressor in early stages but promoted cancer in later stages, similar to other proteins like TGF-β. This dual role makes it a potential target for personalized therapies. The study suggests that lactylation-based gene signatures, especially DHRS7, could serve as biomarkers for prognosis and guide immunotherapy or metabolism-focused treatments in STAD. However, further research is needed to validate these findings and explore DHRS7's mechanisms.

Leonurine Alleviates DSS-Induced Colitis in Mice

Leonurine, an active compound derived from *Leonurus japonicus*, has shown significant potential in alleviating DSS-induced ulcerative colitis (UC) in mice. The study utilized a 3% dextran sulfate sodium (DSS) solution to induce colitis, replicating symptoms of human UC, including inflammation and epithelial barrier damage. Oral administration of leonurine (30 mg/kg/day) for 7 days markedly reduced symptoms such as body weight loss, colon shortening, and disease activity index (DAI) scores. Histopathological analysis revealed reduced epithelial cell loss, crypt damage, and inflammatory infiltration, improving colon tissue structure. Leonurine enhanced intestinal barrier function by upregulating tight junction proteins claudin-1 and occludin, reducing permeability caused by DSS. ELISA tests demonstrated decreased serum levels of proinflammatory cytokines TNF-α and IL-1β, indicating its anti-inflammatory effects. Transmission electron microscopy confirmed preserved tight junction integrity, preventing structural damage caused by DSS. Transcriptomic analysis revealed 861 differentially expressed genes, with significant modulation of pathways related to leukocyte chemotaxis, extracellular matrix organization, and pancreatic secretion. Leonurine downregulated pancreatic protease genes *Cela2a* and *Cela3b*, implicated in gut inflammation and barrier disruption. Quantitative PCR validated these findings. Leonurine also modulated gut microbiota composition, reducing inflammatory bacterial genera such as *Rikenellaceae_RC9_gut_group*, *UBA1819*, *Enterococcus*, and *Oscillibacter*. It increased the abundance of anti-inflammatory Verrucomicrobia, promoting microbial balance. By regulating pancreatic enzymes and microbial composition, leonurine restored intestinal homeostasis, limited bacterial translocation, and protected gut barrier function. These findings highlight its therapeutic potential as a natural candidate for UC treatment, warranting further research into its mechanisms in pancreatic-gut axis regulation.

TREM2 Loss Drives IL-1β+ Macrophage–Mediated Inflammation and Tumor Progression in Pancreatic Cancer

TREM2, a receptor expressed on tumor-associated macrophages (TAMs), plays a critical role in pancreatic ductal adenocarcinoma (PDAC). Researchers explored its function by genetically removing TREM2 in a transgenic mouse model (KPPC;Trem2−/−) to study PDAC progression. Surprisingly, the absence of TREM2 accelerated tumor growth and reduced survival, showing that TREM2 has a protective, anti-inflammatory role rather than promoting cancer. Single-cell RNA sequencing revealed that TREM2 depletion caused an increase in proinflammatory macrophages, leading to chronic inflammation in the tumor microenvironment. Mechanistic studies identified TREM2 as a key regulator that suppresses the NLRP3/NF-κB/IL-1β inflammasome pathway, preventing excessive inflammatory signaling. Without TREM2, this pathway becomes overactive, driving harmful inflammation. Additionally, microbial lipopolysaccharide (LPS) from the gut microbiome worsened inflammation in TREM2-deficient mice, further increasing IL-1β levels and accelerating PDAC progression. This highlights the connection between the gut microbiome and cancer-related inflammation. Importantly, researchers found that blocking IL-1β or depleting the microbiome reversed the rapid tumor progression caused by TREM2 loss, emphasizing the pathogenic role of IL-1β in PDAC. These findings suggest that TREM2 functions as an anti-inflammatory checkpoint, maintaining immune balance by controlling macrophage-driven inflammation. Clinically, targeting the IL-1β pathway or modulating TREM2 activity could offer new therapeutic strategies to reduce inflammation and improve outcomes in pancreatic cancer patients. This research redefines the role of TREM2 in PDAC and opens the door for novel approaches to combat tumor-promoting inflammation.

Role of YAP1 in Pancreatic Cancer

Yes-associated protein 1 (YAP1) is a key regulator in the Hippo signaling pathway, a pathway crucial for controlling cell growth, tissue development, and organ size. In cancer, including pancreatic ductal adenocarcinoma (PDAC), YAP1 becomes dysregulated, playing a significant role in tumor progression, metastasis, and immune evasion. It acts as a transcriptional co-activator, promoting the expression of genes that drive cancer cell proliferation, survival, and resistance to therapies. In PDAC, YAP1 is closely linked to epithelial–mesenchymal transition (EMT), a biological process where cancer cells lose their epithelial characteristics and gain mesenchymal traits, making them more motile and invasive. YAP1 interacts with transcription factors like ZEB1 to enhance EMT, leading to metastatic plasticity, which allows pancreatic cancer cells to spread to other organs more effectively. YAP1 also contributes to immune suppression in PDAC by promoting the secretion of immunosuppressive cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8). These cytokines cause T-cell exhaustion and recruit regulatory immune cells, helping the tumor evade immune system attacks. Furthermore, YAP1 directly increases PD-L1 expression on tumor cells, enabling them to escape destruction by T-cells. Recent research has uncovered that YAP1 undergoes glutamylation—a protein modification—regulated by the enzyme GLS2, which enhances its activity. This modification promotes YAP1’s nuclear translocation, driving the expression of survival genes like PD-L1 and worsening immune evasion. Targeting YAP1 and its associated pathways offers great potential for improving PDAC treatment, especially in overcoming resistance to immunotherapy.

TL1A–DR3 Signaling and Experimental Crohn’s Disease

The TL1A–DR3 signaling pathway plays a central role in the development and progression of Crohn’s disease (CD), a chronic inflammatory condition of the intestines. Research has shown that TL1A activates DR3, a receptor that drives proinflammatory immune responses, particularly through T helper 9 (Th9) cells. These Th9 cells produce interleukin-9 (IL-9), a key inflammatory cytokine that contributes to intestinal damage and inflammation in CD. Using experimental models, researchers studied mice with Crohn’s-like ileitis (SAMP1/YitFc) and DR3-deficient mice to understand the role of this pathway. DR3-deficient mice exhibited reduced intestinal inflammation, lower IL-9 levels, and improved histology, highlighting DR3’s role in sustaining immune hyperactivation. Neutralizing IL-9 with antibodies significantly alleviated inflammation and tissue damage, confirming IL-9’s importance in disease progression. Under Th9-polarizing conditions, DR3 was essential for inducing IL-9 production. Wild-type Th9 cells (Th9^WT) showed high levels of IL-9 and other inflammatory cytokines, while DR3-deficient Th9 cells (Th9^KO) shifted toward an anti-inflammatory phenotype, producing more IL-10. Molecular studies revealed that DR3 deficiency suppressed proinflammatory genes and pathways, including JAK/STAT and PI3K–AKT, while enhancing regulatory markers like Foxp3 and IL-10. Human studies validated these findings, showing upregulation of Th9-related genes in Crohn’s disease patients, linking the TL1A–DR3–IL-9 axis to human intestinal inflammation. Therapeutically, targeting DR3 or IL-9 could provide a novel approach to treat Crohn’s disease by reducing Th9-driven inflammation and restoring immune balance.

TL1A/DR3 signaling and Crohn’s disease

The TL1A/DR3 signaling pathway plays a critical role in driving Crohn’s disease-like intestinal inflammation by regulating the formation and pathogenicity of Th9 cells. Th9 cells, a subset of T helper cells, produce the proinflammatory cytokine IL9, which is central to the inflammatory processes in Crohn’s disease. Functional DR3 signaling enhances the inflammatory capacity of Th9 cells, while its absence shifts Th9 cells toward a regulatory phenotype, reducing inflammation. DR3-deficient Th9 cells exhibit downregulation of proinflammatory genes (e.g., Spi1, Batf3) and upregulation of regulatory genes (e.g., Il10, Foxp3), promoting immune tolerance. DR3 activation engages key pathways such as JAK–STAT, PI3K–AKT, and TCR signaling, amplifying cytokine production and pathogenic T-cell function. Additionally, DR3 signaling inhibits the Hippo–YAP/TAZ pathway, impairing epithelial repair and favoring chronic inflammation. It also polarizes macrophages toward a proinflammatory M1 phenotype, exacerbating tissue damage. In Crohn’s-like ileitis models (e.g., SAMP1/YitFc mice), adoptive transfer of Th9 cells with functional DR3 (Th9WT) caused severe intestinal inflammation, while DR3-deficient Th9 cells (Th9KO) led to minimal inflammation. Blocking IL9 in these models significantly reduced inflammation, highlighting its therapeutic potential. Human studies confirm the relevance of this pathway, with elevated levels of IL9, SPI1, BATF3, and STAT6 observed in Crohn’s and ulcerative colitis patients. The TL1A/DR3/Th9 axis represents a novel immune mechanism driving chronic intestinal inflammation and fibrosis. Targeting DR3 or IL9 signaling offers a promising therapeutic strategy to restore immune balance and treat Crohn’s disease.

KRASG12D mutant cells, pancreatic cell, and Wnt5a signaling

KRASG12D mutant cells are a type of genetically altered pancreatic cells that play a key role in pancreatic cancer development, specifically pancreatic ductal adenocarcinoma (PDAC). Normally, the pancreas has protective mechanisms to eliminate mutant cells to maintain healthy tissue and prevent cancer. However, KRASG12D mutant cells manage to bypass these natural elimination systems and persist in the pancreas. The study found that Wnt5a signaling is crucial for helping KRASG12D mutant cells survive. Wnt5a is part of the noncanonical Wnt signaling pathway, which is different from the β-catenin-dependent pathway. In KRASG12D mutant cells, Wnt5a signaling stabilizes cell junctions by increasing E-cadherin and β-catenin levels, making the cells stick together more tightly. This prevents their expulsion from the pancreatic tissue. Additionally, Wnt5a suppresses E-cadherin internalization, reducing the cells' motility and anchoring them in place. KRASG12D cells also enter a state of dormancy, where they stop dividing but remain alive. This dormancy is marked by high levels of proteins like p27 and Sox9, which protect the cells from immune clearance and apoptosis (cell death). Dormancy allows these mutant cells to survive long-term and gain stem-like properties, increasing their tumor-initiating potential. When KRASG12D is combined with another mutation, p53R172H, the elimination of mutant cells is completely blocked, leading to preneoplastic lesions and tumors. Targeting Wnt5a signaling or reversing dormancy could potentially prevent these mutant cells from surviving and progressing into cancer, offering new therapeutic strategies for pancreatic cancer.

cysteine-rich diet and Intestinal Regeneration- MIT study

The study conducted by researchers at MIT’s Koch Institute for Integrative Cancer Research, led by Dr. Ömer Yilmaz and postdoc Fangtao Chi, has unveiled groundbreaking insights into how a cysteine-rich diet can enhance intestinal tissue regeneration. Below is a detailed overview of the study and its implications: ### **Key Findings** 1. **Cysteine's Role in Regeneration:** - Cysteine, an amino acid, was found to significantly boost the ability of intestinal stem cells to divide and repair damage after injury. - It activates an immune signaling pathway that promotes intestinal stem cell growth and tissue repair. 2. **Healing Radiation Damage:** - The cysteine-rich diet helped repair intestinal lining injured by radiation exposure, which is a common side effect of cancer therapies. 3. **Recovery After Chemotherapy:** - Early data suggest that cysteine also aids recovery following chemotherapy treatments, such as those involving the drug 5-fluorouracil. 4. **Immune System Activation:** - Cysteine triggers CD8+ T cells, which then produce the regenerative cytokine IL-22. - IL-22 stimulates stem cell renewal and tissue repair, enhancing the intestine’s resilience to injury. 5. **Biochemical Pathway:** - Upon absorption, cysteine converts to Coenzyme A (CoA), which activates CD8 T cells to release IL-22. - This immune activation occurs primarily in the small intestine, where protein digestion and absorption are concentrated. 6. **Localized Effect:** - The regenerative effects of cysteine were restricted to the small intestine and did not extend to other parts of the digestive system. ### **Experimental Model** - The research was conducted on mice, providing foundational evidence for potential applications in humans. - The study demonstrated that dietary cysteine can directly influence immune–stem cell interactions to promote tissue healing. ### **Food Sources of Cysteine** - Cysteine is naturally abundant in various foods, including: - Meat - Dairy products - Legumes - Nuts - While the body can produce cysteine from methionine, dietary cysteine offers a more direct enrichment for the intestinal lining. ### **Additional Benefits** 1. **Antioxidant Properties:** - Cysteine’s known antioxidant effects may further protect intestinal cells from oxidative damage. 2. **Stem Cell Niche Expansion:** - The cysteine diet increases the population of IL-22-producing CD8 T cells, enhancing the regenerative potential of the intestinal stem cells. ### **Clinical Implications** - **Safe Therapeutic Option:** - Since cysteine is a natural dietary compound rather than a synthetic drug, it represents a safe and accessible therapeutic possibility. - **Applications in Cancer Recovery:** - Cysteine-enriched diets or supplements could potentially help patients recover from radiation or chemotherapy-induced intestinal injury. - **Future Directions:** - Researchers aim to investigate whether cysteine can stimulate regeneration in other stem cell types, such as hair follicles or other tissues. ### **Mechanistic Insight** - The study provides a deeper understanding of how a single amino acid can directly influence immune–stem cell interactions to promote tissue healing. It highlights the interplay between dietary nutrients, immune activation, and stem cell function. ### **Conclusion** This research opens up exciting possibilities for using cysteine-rich diets as a therapeutic tool to enhance intestinal regeneration, particularly for patients undergoing cancer treatments like radiation and chemotherapy. By leveraging a natural dietary compound, this approach provides a promising avenue for improving recovery and resilience in the small intestine. Future studies will further explore its broader applications in regenerative medicine.

Epithelial-to-Mesenchymal Transition (EMT) and Pancreatic Malignancy

### **Epithelial-to-Mesenchymal Transition (EMT) and Pancreatic Malignancy** Epithelial-to-Mesenchymal Transition (EMT) is a fundamental biological process that plays a pivotal role in the progression of pancreatic malignancy, particularly **pancreatic ductal adenocarcinoma (PDAC)**—the most common and aggressive form of pancreatic cancer. EMT enables cancer cells to acquire invasive and metastatic properties, contributes to therapy resistance, and is associated with poor prognosis. Below is a detailed explanation of EMT and its role in pancreatic malignancy. --- ### **What is EMT?** EMT is a process in which epithelial cells lose their defining characteristics—such as cell-cell adhesion and polarity—and gain mesenchymal traits, including enhanced motility, invasiveness, and resistance to apoptosis. This transition is critical for normal developmental processes like embryogenesis but is hijacked by cancer cells during tumor progression. #### **Key Features of EMT** 1. **Loss of Epithelial Traits**: - Downregulation of epithelial markers such as **E-cadherin**, a cell adhesion molecule critical for maintaining epithelial integrity. - Loss of apical-basal polarity, which is essential for epithelial tissue organization. 2. **Acquisition of Mesenchymal Traits**: - Upregulation of mesenchymal markers such as **vimentin**, **fibronectin**, and **N-cadherin**. - Enhanced migratory and invasive capabilities, enabling cancer cells to spread to distant sites. 3. **Regulation by EMT Transcription Factors**: - EMT is governed by transcription factors like **Snail**, **Slug**, **Twist**, **ZEB1**, and **ZEB2**, which suppress epithelial genes and activate mesenchymal genes. 4. **Signaling Pathways Driving EMT**: - **TGF-β Pathway**: A central regulator of EMT in pancreatic cancer. - **Wnt/β-catenin Pathway**: Stabilizes β-catenin, leading to activation of EMT-related transcription factors. - **Notch Pathway**: Promotes EMT-associated gene expression. - **NF-κB Pathway**: Induces inflammatory cytokines that enhance EMT. - **Ras/MAPK Pathway**: Frequently activated in PDAC, driving EMT and tumor progression. --- ### **Role of EMT in Pancreatic Malignancy** #### **1. Tumor Progression** EMT is a key driver of pancreatic cancer progression, enabling cancer cells to invade surrounding tissues and metastasize to distant organs. - **Invasion and Metastasis**: - EMT allows cancer cells to detach from the primary tumor, degrade the extracellular matrix (ECM), and migrate to distant sites. - Mesenchymal-like cells are better equipped to invade blood vessels and lymphatic systems, facilitating metastatic spread. - **Cancer Stem Cells (CSCs)**: - EMT generates cells with stem-like properties, termed **cancer stem cells (CSCs)**. - CSCs contribute to tumor initiation, self-renewal, and resistance to conventional therapies. #### **2. Therapy Resistance** EMT is closely linked to the development of resistance to chemotherapy and immunotherapy in pancreatic cancer. - **Chemoresistance**: - EMT-associated cancer cells exhibit reduced apoptosis and increased drug efflux via ATP-binding cassette (ABC) transporters. - Transcription factors like **ZEB1** suppress pro-apoptotic genes, enhancing survival mechanisms. - **Immunotherapy Resistance**: - EMT reduces the expression of immune-recognition molecules, allowing tumor cells to evade immune surveillance. #### **3. Tumor Microenvironment (TME)** The tumor microenvironment plays a critical role in driving EMT in pancreatic cancer. - **Pancreatic Stellate Cells (PSCs)**: - PSCs secrete factors like **TGF-β**, which activate EMT in cancer cells. - **Immune Cells**: - Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) secrete cytokines that promote EMT and suppress anti-tumor immunity. --- ### **Molecular Mechanisms of EMT in Pancreatic Cancer** | **Mechanism** | **Description** | |-------------------------------|---------------------------------------------------------------------------------| | **Loss of E-cadherin** | Downregulation of E-cadherin disrupts cell-cell adhesion, promoting invasiveness. | | **TGF-β Signaling** | Activates Smad transcription factors, inducing EMT and promoting metastasis. | | **Wnt/β-catenin Activation** | Stabilizes β-catenin, driving mesenchymal gene expression. | | **ZEB1 and ZEB2** | Suppress epithelial genes and enhance mesenchymal markers. | | **NF-κB Pathway** | Induces inflammatory cytokines that promote EMT and immune evasion. | --- ### **Clinical Implications of EMT in Pancreatic Malignancy** #### **1. Prognostic Marker** - EMT markers, such as **loss of E-cadherin** and **ZEB1 expression**, are associated with poor prognosis in PDAC. - High EMT activity correlates with increased metastasis and reduced survival rates. #### **2. Therapeutic Challenges** - EMT-associated cells are resistant to conventional therapies, contributing to recurrence and progression. - Chemoresistance and immune evasion driven by EMT complicate treatment strategies. #### **3. Therapeutic Targets** Targeting EMT pathways offers promising strategies for improving pancreatic cancer outcomes. - **TGF-β Inhibitors**: - Agents like **fresolimumab** (anti-TGF-β monoclonal antibody) and small molecule inhibitors of TGF-β signaling. - **Wnt/β-catenin Inhibitors**: - Drugs targeting Wnt signaling to suppress EMT and stemness. - **NF-κB Inhibitors**: - Agents like **BAY 11-7082** to block inflammatory EMT signaling. - **Epigenetic Modulators**: - Drugs targeting EMT transcription factors (e.g., ZEB1/Slug inhibitors). --- ### **Challenges in Targeting EMT** #### **1. Plasticity** - EMT is reversible; cells can transition back to epithelial phenotypes via **mesenchymal-to-epithelial transition (MET)**. - This plasticity makes it difficult to permanently target EMT-associated cells. #### **2. Off-Target Effects** - Systemic inhibition of EMT pathways may disrupt normal tissue repair and immune responses. #### **3. Heterogeneity** - EMT-associated cells exhibit heterogeneity, complicating the development of universal therapies. --- ### **Key Points for Understanding EMT in Pancreatic Cancer** 1. **Definition**: EMT is a process where epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness. 2. **Markers**: Loss of epithelial markers (e.g., E-cadherin) and upregulation of mesenchymal markers (e.g., vimentin, N-cadherin). 3. **Signaling Pathways**: TGF-β, Wnt/β-catenin, Notch, NF-κB, and Ras/MAPK are key drivers of EMT in pancreatic cancer. 4. **Role in PDAC**: - Promotes invasion, metastasis, chemoresistance, and immune evasion. - Generates cancer stem cells, contributing to tumor progression. 5. **Therapeutics**: - TGF-β inhibitors, Wnt inhibitors, NF-κB blockers, and epigenetic modulators are under investigation. --- ### **Takeaway Box** - **EMT in Pancreatic Cancer**: - EMT is a critical mechanism driving metastasis, chemoresistance, and poor prognosis in PDAC. - It generates cancer stem cells and interacts with the tumor microenvironment to exacerbate disease progression. - **Therapeutic Potential**: - Targeting EMT pathways (e.g., TGF-β, Wnt/β-catenin) offers promise but faces challenges like plasticity, heterogeneity, and off-target effects. Understanding EMT's role in pancreatic malignancy provides valuable insights into the aggressive nature of PDAC and highlights potential therapeutic strategies to combat this deadly disease.

PDGFRβ and GSK3β: Fidaxomicin’s Role in Intestinal Fibroblasts

### PDGFRβ and GSK3β: Key Players in Intestinal Fibrosis #### **PDGFRβ (Platelet-Derived Growth Factor Receptor Beta):** - **Function:** PDGFRβ is a receptor tyrosine kinase that plays a critical role in cellular signaling, particularly in fibroblast activation, proliferation, and migration. It regulates tissue remodeling, wound healing, and extracellular matrix production. - **Role in Fibrosis:** In Crohn’s disease (CD), PDGFRβ is strongly overexpressed in fibrotic intestinal regions, driving fibroblast activation and excessive collagen deposition, which contributes to intestinal fibrosis. - **Mechanism:** Upon binding its ligand, PDGF-BB, PDGFRβ undergoes phosphorylation, triggering downstream signaling pathways that promote fibrogenesis, including activation of the GSK3β pathway. #### **GSK3β (Glycogen Synthase Kinase 3 Beta):** - **Function:** GSK3β is a serine/threonine kinase involved in various cellular processes, including inflammation, cell proliferation, and differentiation. It also regulates collagen synthesis and extracellular matrix remodeling. - **Role in Fibrosis:** In CD-associated fibrosis, GSK3β is activated downstream of PDGFRβ signaling. Phosphorylation of GSK3β contributes to fibroblast activation and collagen production, exacerbating fibrotic progression. - **Signaling Axis:** PDGFRβ–GSK3β signaling is central to fibrogenesis. Inhibiting this pathway can suppress fibroblast activation and collagen deposition. --- ### Fidaxomicin’s Role in Intestinal Fibroblasts #### **Overview of Fidaxomicin:** - Fidaxomicin is an FDA-approved antibiotic primarily used to treat Clostridioides difficile infections. It has a gut-restricted bioactivity, meaning it acts locally in the gastrointestinal tract without systemic absorption. #### **Antifibrotic Mechanism in Intestinal Fibroblasts:** 1. **Targeting PDGFRβ:** - Fidaxomicin binds strongly to PDGFRβ, as confirmed by molecular docking studies (binding energy: −8.5 kcal/mol). - It inhibits PDGFRβ phosphorylation, effectively downregulating PDGFRβ signaling. - This results in reduced activation of intestinal fibroblasts and suppression of collagen gene expression (e.g., COL1A1 and COL1A2), thereby mitigating fibrosis. 2. **Modulation of GSK3β:** - Fidaxomicin suppresses GSK3β phosphorylation induced by patient-derived exosomes (CDSE), which is dependent on PDGFRβ modulation. - This action further inhibits fibroblast activation and collagen synthesis, confirming the PDGFRβ–GSK3β signaling axis as a therapeutic target. 3. **Gene Expression Suppression:** - Fidaxomicin downregulates key fibrosis-related genes, including **COL1A1**, **COL1A2**, and **PDGFRB**, in patient-derived explants. - Importantly, it does not affect fibroblast migration or epithelial-mesenchymal transition, suggesting its effects are specific to fibrogenesis. #### **Combined Antifibrotic and Anti-Inflammatory Effects:** - Fidaxomicin reduces inflammatory markers such as IL-8 and TNF-α in peripheral blood mononuclear cells, indicating dual antifibrotic and anti-inflammatory properties. - This makes it particularly suited for treating fibrostenotic Crohn’s disease, which involves both fibrosis and inflammation. #### **In Vivo Efficacy:** - In the SAMP1/YitFc CD mouse model: - Oral fidaxomicin significantly lowered fibrosis scores and collagen gene expression. - It reduced overall disease activity without altering the gut microbiota, showcasing its safety and tolerability. #### **Mechanistic Specificity:** - Overexpression of **Pdgfrb** or **Gsk3b** nullified fidaxomicin’s antifibrotic effects, confirming the critical roles of these targets in its mechanism of action. --- ### **Therapeutic Potential of Fidaxomicin:** - Fidaxomicin’s gut-restricted bioactivity, strong antifibrogenic efficacy, and safety profile position it as a promising candidate for targeted therapy in fibrostenotic Crohn’s disease. - By inhibiting the PDGFRβ–GSK3β signaling axis, fidaxomicin addresses the therapeutic gap in treating intestinal fibrosis, which current anti-inflammatory agents fail to achieve.

Human Gut Mycobiome (Gut Fungi)

The human gut mycobiome refers to the community of fungi residing within the gastrointestinal tract. Though less studied than the bacterial microbiome, the fungal component plays a significant role in gut health, immune regulation, and disease outcomes. Here’s a detailed overview: ### **Key Fungi in the Gut Mycobiome** 1. **Candida Genus**: - **Candida albicans**: This is a common lifelong colonizer of the human gut. It exists in two forms: - **Yeast form**: Benign and less harmful. - **Hyphal form**: Pathogenic and associated with intestinal inflammation and diseases like inflammatory bowel disease (IBD). Hyphae produce adhesins and cytolytic toxins that contribute to pathogenicity. - **Candida dubliniensis**: In young, antibiotic-exposed mice, colonization with this species has been shown to enhance pancreatic beta-cell development and reduce the risk of diabetes. - **Candida glabrata**: Another species that may induce immune responses, such as IgA production, though its pathogenic potential is less understood compared to C. albicans. 2. **Saccharomyces Genus**: - Includes beneficial fungi like **Saccharomyces cerevisiae**, which may promote metabolic health. 3. **Malassezia Genus**: - Typically found on the skin but also present in the gut, its exact role in gut health is still being explored. ### **Fungal Immune Interactions** - Fungi stimulate distinct immune pathways compared to bacteria. Some fungi promote metabolic health, while others exacerbate inflammation. - **Candida albicans** can drive intestinal inflammation, especially in its pathogenic hyphal form. The immune system combats this through: - **IgA antibodies**: These selectively target fungal adhesins and cytolytic toxins to prevent overgrowth and pathogenic transitions. - **IgA Deficiency**: Linked to C. albicans overgrowth, which can worsen inflammatory conditions like IBD. ### **Therapeutic Insights** 1. **Vaccines**: - **NDV-3A Vaccine**: Developed to target fungal adhesins, this vaccine induces adhesin-specific IgA responses. In mouse models, it has been shown to protect against fungal-driven colitis caused by C. albicans. 2. **Targeted Therapies**: - Understanding the strain-specific and morphology-specific roles of fungi in the gut may allow for precision therapies in conditions like IBD and cancer. ### **Potential Health Impacts** - **Metabolic Health**: Certain fungi, such as Candida dubliniensis, may have protective roles in metabolic diseases like diabetes. - **Inflammation and IBD**: Pathogenic fungi, particularly C. albicans in its hyphal form, can exacerbate gut inflammation and contribute to diseases like IBD. - **Cancer**: Emerging research suggests that fungal components of the gut microbiome may influence cancer development and progression, though mechanisms remain under investigation. ### **Research Implications** The human gut mycobiome is a promising area of study with implications for understanding host-microbe interactions, immune modulation, and the development of novel therapies for chronic diseases. By identifying the specific roles of fungal strains and their morphological states, researchers can better target interventions to improve gut health and treat related conditions.

Molecular Diagnostic Algorithm Identifying Rat Hepatitis E Virus (GEHEP-014 Study)

The **GEHEP-014 Study** focuses on the development and optimization of a molecular diagnostic algorithm to detect **rat hepatitis E virus (ratHEV)** as a potential cause of unexplained acute hepatitis. This multicenter study highlights the importance of including ratHEV in the differential diagnosis of acute hepatitis, especially given its zoonotic potential and the associated morbidity and mortality. ### Key Findings of the GEHEP-014 Study: 1. **Study Population**: - The study analyzed samples from **562 patients** with unexplained acute hepatitis. - These patients had no prior diagnosis or established cause for their liver inflammation, making them ideal candidates for investigating emerging pathogens like ratHEV. 2. **Molecular Diagnostic Algorithm**: - The study utilized advanced molecular diagnostic techniques, including **polymerase chain reaction (PCR)** and **sequencing**, to detect ratHEV RNA in patient samples. - Positive cases underwent further **phylogenetic analysis** to confirm the virus and to compare it with known ratHEV strains. 3. **Detection Rate**: - RatHEV RNA was confirmed in **1.4% of the patients** (approximately 8 cases out of 562). - This highlights that while ratHEV is not a predominant cause of acute hepatitis, it is an **underdiagnosed and emerging pathogen**. 4. **Clinical Outcomes**: - Among the confirmed cases, patients experienced **significant morbidity**, requiring hospitalization. - There was **one fatality**, underscoring the potential severity of ratHEV infection in humans. 5. **Zoonotic Transmission**: - Phylogenetic analysis revealed that the detected ratHEV strains were closely related to strains found in local rodent populations. - This strongly supports the hypothesis of **zoonotic transmission**, where the virus is transmitted from rodents to humans. 6. **Public Health Implications**: - The study establishes ratHEV as an **important and emerging cause of acute hepatitis**. - It emphasizes the need to include ratHEV in the **routine differential diagnosis** of acute hepatitis, particularly in cases with no known etiology. ### Importance of the Study: - **Emerging Pathogen**: RatHEV has been largely overlooked in clinical diagnostics, but the GEHEP-014 study identifies it as a relevant cause of acute hepatitis in humans. - **Diagnostic Advances**: The study demonstrates the value of molecular diagnostic tools, such as PCR and sequencing, in detecting rare or novel pathogens. - **Zoonotic Risk**: The close genetic relationship between human and rodent strains highlights the public health risk posed by zoonotic pathogens, particularly in areas with high rodent populations. - **Clinical Awareness**: Healthcare providers should consider ratHEV in patients with unexplained acute hepatitis, especially if there is a history of potential exposure to rodents. ### Conclusion: The **GEHEP-014 study** provides critical insights into the role of ratHEV in acute hepatitis and underscores the need for heightened clinical awareness and improved diagnostic protocols. By incorporating molecular diagnostics into routine practice, healthcare systems can better identify and manage cases of ratHEV, reducing the risk of severe outcomes and improving patient care.

Oral Microbiome Dysbiosis and Precancerous Lesions of the Upper GI Tract

The study highlights the relationship between oral microbiome dysbiosis and the development of precancerous lesions in the upper gastrointestinal (GI) tract. Dysbiosis refers to an imbalance in the microbial community, and in this context, it is associated with various upper GI disorders that may precede cancer, such as reflux, esophagitis, Barrett’s esophagus, and gastric conditions like atrophic gastritis. ### Key Findings: 1. **Salivary Dysbiosis:** - Imbalances in the salivary microbiome were linked to conditions such as reflux, esophagitis, Barrett’s esophagus, and other gastric disorders. - Saliva serves as a general indicator of systemic and upper GI health. 2. **Site-Specific Dysbiosis:** - Dysbiosis in the subgingival (below the gumline) and buccal mucosal (inner cheek) microbiomes was more specifically associated with Barrett’s esophagus and atrophic gastritis. - These site-specific microbial changes suggest that the oral microbiome's composition varies depending on the disease and its location. 3. **Microbial Signatures:** - Disease states were characterized by an **enrichment of harmful bacteria** like *Prevotella*, *Fusobacterium*, and *Fretibacterium*. - There was also a **depletion of protective bacteria** such as *Haemophilus*, which are thought to contribute to maintaining oral and systemic health. 4. **Cancer Risk Prediction:** - Among the oral microbiomes studied, the **subgingival microbiota** demonstrated the greatest potential as a biomarker for predicting cancer risk. - This suggests that microbial imbalances in subgingival sites might be early indicators of esophageal and gastric cancer development. ### Implications: - **Non-Invasive Biomarkers:** The findings support the development of non-invasive diagnostic tools based on oral microbiome analysis. This could enable early detection of esophageal and gastric cancers, improving patient outcomes. - **Targeted Interventions:** Understanding the specific microbial changes associated with different precancerous lesions may allow for targeted prevention strategies, such as microbiome modulation through probiotics, oral hygiene practices, or dietary changes. ### Conclusion: The study underscores the importance of the oral microbiome in the pathogenesis of upper GI tract disorders and its potential role in cancer risk assessment. Site-specific dysbiosis, particularly in the subgingival microbiota, offers promising avenues for developing early detection methods and preventive measures for esophageal and gastric cancers.

Stromal Stiffness and Immune Evasion in Pancreatic Cancer

Stromal stiffness plays a critical role in promoting immune evasion in pancreatic ductal adenocarcinoma (PDAC). The study highlights a mechanistic link between the tumor microenvironment, particularly stromal stiffness, and immune resistance through an epigenetic-metabolic pathway. ### Key Findings: 1. **Role of IGF2BP2 in Immune Evasion**: - IGF2BP2, an m6A RNA-binding protein, was identified as a mediator of immune evasion in PDAC. - It stabilizes the transcripts of **SGMS2**, an enzyme involved in sphingomyelin synthesis, which is crucial for immune resistance. 2. **Mechanism of Immune Evasion**: - SGMS2 promotes the synthesis of sphingomyelin, a lipid that enhances the localization of **PD-L1** in lipid rafts. - PD-L1 in lipid rafts suppresses T-cell infiltration and activity, enabling the tumor to evade immune detection and destruction. 3. **Impact of Stromal Stiffness**: - The stiff extracellular matrix (ECM) in the tumor microenvironment prevents the degradation of IGF2BP2, leading to its upregulation. - This links stromal stiffness to increased IGF2BP2 activity, enhanced SGMS2 expression, and subsequent immune suppression. 4. **Therapeutic Implications**: - Dual inhibition of IGF2BP2 and SGMS2 was shown to reverse immune evasion in preclinical models. - This approach restored T-cell infiltration and activity, improved cytokine production, and prolonged survival in animal models of PDAC. ### Broader Significance: The study uncovers a **stiffness-driven epigenetic-metabolic pathway** that underpins immune escape in pancreatic cancer. It provides insights into how the physical properties of the tumor microenvironment contribute to immune resistance, offering novel therapeutic targets. Targeting IGF2BP2 and SGMS2 could enhance the efficacy of immunotherapy in PDAC, a cancer type notoriously resistant to immune-based treatments. This research emphasizes the importance of addressing not only the biological but also the mechanical aspects of the tumor microenvironment to combat immune evasion in pancreatic cancer.

Peripheral Blood DNA Methylation Signatures to Predict Biologic Response in Crohn’s Disease (EPIC-CD)

The EPIC-CD study (Peripheral Blood DNA Methylation Signatures to Predict Biologic Response in Crohn’s Disease) investigated the potential of using baseline DNA methylation profiles in peripheral blood to predict how patients with Crohn's disease would respond to biologic therapies. The study focused on three biologics commonly used in Crohn's disease management: vedolizumab, ustekinumab, and adalimumab. ### Key Findings: 1. **Predictive Capability of DNA Methylation Profiles**: - DNA methylation profiles at baseline were able to predict treatment response to **vedolizumab** and **ustekinumab** with significant accuracy. - These profiles, however, were **not predictive** of response to **adalimumab**. 2. **Stronger Predictive Accuracy in Anti-TNF-Naive Patients**: - The predictive accuracy of DNA methylation models was strongest among patients who were **anti-TNF-naive** (i.e., those who had not previously been treated with tumor necrosis factor inhibitors like adalimumab). - This suggests that the epigenetic signatures may be more reliable in patients who have not yet been exposed to anti-TNF therapies. 3. **Comparison with Existing Clinical Tools**: - DNA methylation models **outperformed existing clinical decision tools** for predicting treatment response. - This highlights the potential of DNA methylation as a more precise biomarker for guiding therapy selection. 4. **Validation and Consistency**: - The study validated the findings and confirmed that the predictive performance for **vedolizumab** and **ustekinumab** was consistent. - This strengthens the reliability of DNA methylation as a biomarker for these two therapies. ### Implications: - **Personalized Therapy in Crohn’s Disease**: - The ability to predict treatment response using DNA methylation signatures provides a pathway for **personalized therapy selection**. This could improve treatment outcomes by ensuring that patients are matched with the biologic therapy most likely to be effective for them. - **Reducing Ineffective Drug Exposure**: - By identifying patients unlikely to respond to certain biologics (e.g., adalimumab), clinicians can avoid exposing these patients to ineffective treatments, reducing unnecessary side effects and healthcare costs. - **Future Applications**: - The findings suggest that DNA methylation profiling could become an important tool in precision medicine for Crohn’s disease, potentially integrated into clinical practice to optimize treatment strategies. ### Limitations and Next Steps: - The study did not find predictive utility for adalimumab, suggesting that further research is needed to understand why this biologic does not align with DNA methylation profiles. - Larger, multi-center studies may be required to confirm these findings and assess their generalizability across diverse populations. - Development of standardized protocols for DNA methylation analysis will be crucial for translating these findings into clinical practice. In summary, the EPIC-CD study highlights the promise of using peripheral blood DNA methylation signatures to predict response to vedolizumab and ustekinumab in Crohn’s disease. This represents a significant step toward precision medicine, enabling more tailored and effective treatment approaches for patients.

Cendakimab in Adults and Adolescents with Eosinophilic Esophagitis

Cendakimab, an interleukin-13 (IL-13)–blocking monoclonal antibody, has shown promising results in the treatment of eosinophilic esophagitis (EoE) in adults and adolescents. EoE is a chronic, immune-mediated condition characterized by inflammation of the esophagus, leading to symptoms such as dysphagia (difficulty swallowing), food impaction, and other esophageal dysfunctions. The disease is associated with eosinophilic infiltration of the esophageal lining, and IL-13 plays a key role in driving this inflammatory response. ### Key Findings from the Phase 3 Trial: 1. **Symptom Reduction**: - Cendakimab demonstrated significant efficacy in reducing dysphagia, one of the most troubling and common symptoms of EoE. This improvement was clinically meaningful for patients, enhancing their ability to eat and swallow more comfortably. 2. **Histologic Response**: - The treatment led to marked improvements in histologic outcomes, meaning a significant reduction in eosinophilic inflammation in the esophageal tissue. This is a critical measure of disease control in EoE. 3. **Endoscopic Outcomes**: - Cendakimab improved endoscopic findings, such as reducing esophageal rings, furrows, and other visible signs of inflammation and fibrosis commonly seen in EoE patients. 4. **Sustained Efficacy**: - The benefits of cendakimab were sustained over a 48-week treatment period, indicating its potential for long-term management of the disease. 5. **Safety and Tolerability**: - The treatment was generally well tolerated. While adverse events were common, they were not dose-limiting, meaning they did not necessitate discontinuation of the therapy. This highlights the favorable safety profile of cendakimab for long-term use. ### Mechanism of Action: Cendakimab works by blocking IL-13, a cytokine that plays a key role in the pathogenesis of EoE. IL-13 drives eosinophilic inflammation, tissue remodeling, and fibrosis in the esophagus. By inhibiting IL-13, cendakimab targets the underlying immune dysregulation in EoE. ### Implications for Adults and Adolescents with EoE: - **Effective Therapy Option**: Cendakimab offers a new therapeutic option for patients who may not respond adequately to dietary management, proton pump inhibitors (PPIs), or topical corticosteroids, which are the current standard treatments for EoE. - **Long-Term Management**: The sustained efficacy and safety profile support its use as a long-term treatment for managing chronic symptoms and preventing disease progression. - **Improved Quality of Life**: By reducing dysphagia and improving esophageal health, cendakimab has the potential to significantly improve the quality of life for patients with EoE. ### Conclusion: The phase 3 trial results confirm that cendakimab is an effective and safe therapeutic option for adults and adolescents with eosinophilic esophagitis. It addresses key aspects of the disease, including symptom relief, histologic improvement, and endoscopic healing, while offering sustained benefits over time. This positions cendakimab as a valuable addition to the treatment landscape for EoE.