Trending Topics in Gastroenterology | GastroAGI

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.