Trending Topics in Gastroenterology | GastroAGI

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.