Min Shi

Acute-on-chronic liver failure is a severe syndrome with high short-term mortality, and current treatments are limited to liver transplantation and supportive care. Here we show that EP300 inhibition alleviates acute-on-chronic liver failure by targeting scar-associated macrophages, a subset that proliferates during disease progression and whose impaired antibacterial function is linked to poor prognosis. EP300 inhibition enhances the antibacterial activity of scar-associated macrophages through transcriptional repression of ACOD1. ACOD1 expression is induced in scar-associated macrophages during acute-on-chronic liver failure, and its loss mitigates hepatic destruction and prolongs survival in male mice with acute-on-chronic liver failure by enhancing the phagocytic function of scar-associated macrophages. These findings suggest that EP300 inhibition alleviates acute-on-chronic liver failure through ACOD1-dependent reprogramming of scar-associated macrophages, providing a promising therapeutic strategy for acute-on-chronic liver failure.

Background: The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide is increasing rapidly worldwide, and the pancreatic and biliary safety of these drugs has been a concern. This study was based on the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate the pancreatic and biliary adverse event reporting signals of liraglutide, semaglutide, tirzepatide and dulaglutide. Objectives: To describe the reporting patterns of pancreatic and biliary adverse events for liraglutide, semaglutide, dulaglutide, and tirzepatide, and to identify signals in both organ systems within a single framework. Design: Retrospective disproportionality analysis of individual case safety reports. Methods: FAERS data from Q3–2009 through Q3–2025 were extracted, and deduplicated ICSRs were used as the unit of analysis. Reporting odds ratios (RORs) and information components (ICs) were computed at composite and Preferred Term levels; signals required the lower 95% confidence bound for the ROR to exceed 1 and IC025 to exceed 0. Metformin and sodium-glucose cotransporter-2 inhibitors were included as contextual benchmarks. Analyses were stratified by brand (diabetes/obesity indication), sex, age, and reporter type, and time to onset was examined. Results: A disproportionality signal for pancreatic adverse events was observed for all four study drugs, but the control drugs metformin and SGLT2i also showed positive signals. For biliary events, all four study drugs showed signals, whereas the two control drugs showed no signals. After stratification by brand, the pancreatic signal remained for brands with diabetes indications, while the signal was weaker for brands with obesity indications. After excluding the cases of biliary tract co-reporting, the pancreatic signal still existed. Median time to onset ranged from 85.5 to 136 days for pancreatic events and from 146.5 to 320 days for biliary events. Conclusion: Both GLP-1RAs and tirzepatide are associated with disproportionate reporting of pancreatic and biliary adverse events in FAERS. Signals are influenced by indication, reporting behavior, and time effects and cannot be used to estimate incidence or prove causality. These signals suggest the need for further validation in real-world cohort studies.

Extracellular vesicles (EVs) have emerged as versatile biological carriers capable of transporting diverse therapeutic cargos. Their endogenous biogenesis pathways provide unique opportunities to regulate cargo selection through both environmental modulation and genetic programming. This review outlines how EV‐producing cells can be reprogrammed to load functional proteins and nucleic acids by combining environmental cues with genetic modifications that leverage intrinsic sorting machinery and engineered molecular interactions. For protein cargo, we outline strategies that reshape EV composition through physiological stimuli, as well as genetically encoded systems designed to recruit proteins via scaffold fusion, peptide tags, or fusion‐independent mechanisms. For nucleic acid cargo, we highlight approaches that leverage environment‐driven alterations in RNA abundance, together with targeted loading methods that rely on scaffold‐RNA‐binding proteins (RBPs) fusion constructs, natural sorting motifs, and sorting‐related RBPs to enrich miRNAs, mRNAs, and ribonucleoprotein complexes. We further summarize recent therapeutic applications of these endogenous engineering strategies in cardiovascular, hepatic, neurological diseases, and cancer. Finally, we discuss future directions, including high‐throughput discovery of sorting elements, scalable biomanufacturing, and improved standardization, which together will advance the development of programmable and clinically translatable EVs‐based therapeutics.

Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the treatment of hematologic malignancies, but its success in solid tumors, particularly those of the digestive system, remains limited. Tumors of the gastrointestinal system, including gastric, colorectal, esophageal, hepatic, and pancreatic malignancies, represent a significant global health burden with high morbidity and mortality. Recent advances in antigen selection, chimeric antigen receptor design, delivery techniques, and combinatorial approaches have sparked renewed interest in CAR-T immunotherapy for these cancers. This article discusses recent progress in CAR-T development across the major digestive system tumors, outlines tumor-specific targets and clinical trials, highlights prevailing challenges and potential solutions, and proposes strategic directions for the next generation of CAR-T therapies in solid tumors.

Background: Acute-on-chronic liver failure is a fatal syndrome involving sudden hepatic deterioration in patients with chronic liver disease, resulting in high short-term mortality. The intrahepatic molecular mechanisms that drive disease progression are poorly understood, partly due to limited access to human liver tissues. Method: Transcriptomic profiling of liver tissues from patients with hepatitis B virus-related acute-on-chronic liver failure and a corresponding murine model was performed. Comparative analyses were conducted across disease stages to delineate the dynamic immune and metabolic trajectories. Result: The analysis uncovered a conserved immune-metabolic dysregulation during disease progression. In both patients and mice, immune activation-characterized by monocyte and macrophage infiltration and altered cytokine signaling-coincided with progressive metabolic failure, including the suppression of mitochondrial functions. The murine model further demonstrated a transition from an early stage of hyperinflammation to a later stage of immune exhaustion. Moreover, several monocyte and macrophage-associated genes were identified as conserved markers that correlate with disease severity, highlighting their potential as biomarkers or therapeutic targets. Conclusion: This study defines a conserved immune-metabolic interplay during the progression of hepatitis B virus-related acute-on-chronic liver failure and validates the murine model’s accuracy for studying the disease’s terminal stage. The identified dysregulation of immune cells and metabolic pathways presents actionable targets for developing stage-specific therapies intended to disrupt the disease’s vicious immune-metabolic cycle.

Ganoderic acid A (GAA), a major bioactive triterpenoid from Ganoderma lucidum, is known for its anti-inflammatory effects; however, its precise molecular targets in sepsis-related liver injury (SRLI) remain unclear. Integrating network pharmacology and transcriptomic analysis, we identified Tumor Necrosis Factor-alpha (TNFα) as a primary candidate target. Subsequent biophysical validation using surface plasmon resonance (SPR) and molecular dynamics (MD) simulations confirmed that GAA directly binds to TNFα. Functionally, this interaction inhibits the TNFα/NF-κB signaling axis, thereby suppressing macrophage M1 polarization and ameliorating liver injury in vitro and in vivo . This study identifies TNFα as a primary candidate target of GAA, providing a mechanistic basis for its hepatoprotective effects and therapeutic potential.

Colorectal cancer (CRC) is ranked as the third most common tumor globally, representing approximately 10% of all cancer cases, and is the second primary cause of cancer-associated mortality. Existing therapeutic approaches demonstrate limited efficacy against CRC, partially due to the immunosuppressive tumor microenvironment (TME). In recent years, substantial evidence indicates that dysbiosis of the gut microbiota and its metabolic products is closely associated with the initiation, progression, and prognostic outcomes of CRC. In this minireview, we systematically elaborate on how these microbes and their metabolites directly impair intestinal epithelial integrity, activate cancer-associated fibroblasts, remodel tumor vasculature, and critically, sculpt an immunosuppressive landscape by modulating T cells, dendritic cells, and tumor-associated macrophages. We highlight the translational potential of targeting the gut microbiota, including fecal microbiota transplantation, probiotics, and engineered microbial systems, to reprogram the TME and overcome resistance to immunotherapy and chemotherapy. A deeper understanding of the microbiota-TME axis is essential for developing novel diagnostic and therapeutic paradigms for CRC.