Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Augmenter of Liver Regeneration Crotonylation Assists in Mitochondria-ER Contact to Alleviate Hepatic Steatosis","authors":"Xiao-lin Wang ,&nbsp;Jia-hao He ,&nbsp;Ping Xie,&nbsp;Yuan Wu,&nbsp;Ling-yue Dong,&nbsp;Wei An","doi":"10.1016/j.jcmgh.2024.101436","DOIUrl":"10.1016/j.jcmgh.2024.101436","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Crotonylation (Kcr), a newly identified post-translation modification (PTM), has been confirmed to be involved in diverse biological processes and human diseases as well. Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a serious threat to people’s health. Augmenter of liver regeneration (ALR) is an important liver regulatory protein, and the insufficiency of ALR expression is reported to accelerate liver steatosis progression to liver fibrosis or even hepatic carcinoma (HCC). However, the connection between dysregulated ALR crotonylation and MASLD pathogenesis remains largely unknown.</div></div><div><h3>Methods</h3><div>Steatotic liver samples from human and Western diet (WD)-fed mice were employed for detecting Kcr levels. Mitochondrial function and mitochondria-ER interaction (MAM) relevant to ALR-Kcr modification was evaluated for hepatocyte lipid metabolism both in <em>in vivo</em> and <em>in vitro</em> experiments.</div></div><div><h3>Results</h3><div>Global protein crotonylation (Kcr) as well as ALR-Kcr was significantly decreased in liver samples of patients with MASLD and WD mice. Histone deacetylase1/2 (HDAC1/2) and lysine acetyltransferase 8 (KAT8) were identified responsible for regulation of ALR-Kcr, which takes place at lysine 78 (K78). The decrease of ALR crotonylation might be related to the imbalance between HDAC1/2 and KAT8 expression, inhibited its interaction with MFN2, expanding MAM distance and impairing mitochondrial lipid metabolism, and consequently deteriorating hepatic steatosis.</div></div><div><h3>Conclusions</h3><div>The insufficient ALR crotonylation might be a crucial mechanism contributing to the pathogenesis of MASLD. Keeping ALR crotonylation level would be beneficial for the prevention and treatment of MASLD.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101436"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of FOXA3 Overexpression on Hepatocyte Differentiation and Liver Regeneration in a Fah cKO Mouse Model","authors":"Shao Li ,&nbsp;Chupeng Ou ,&nbsp;Jiajun Zhang ,&nbsp;Min Zeng ,&nbsp;Kangyan Liang ,&nbsp;Qing Peng ,&nbsp;Yi Gao","doi":"10.1016/j.jcmgh.2024.101438","DOIUrl":"10.1016/j.jcmgh.2024.101438","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Stimulated by injury or disease, hepatocytes can regenerate and repair liver tissues through proliferation and differentiation. Partial hepatectomy and liver transplantation are effective treatments for liver diseases. This study investigated the effect of FOXA3 on cell differentiation in HepaRG cell lines under 2- and 3-dimensional culture conditions.</div></div><div><h3>Methods</h3><div>Experiments were performed using a HepaRG cell line that stably overexpressed FOXA3 (RF3) and hepatocyte-specific functions. Moreover, a Fah conditional knockout mouse model (Fah cKO mice) was constructed using the CRISPR-Cas9 method and treated with RF3 spheroids for transplantation. Various molecular biology and immunostaining experiments were performed to assess liver function, hepatocyte structure, and expression levels of cell cycle–related proteins.</div></div><div><h3>Results</h3><div>HepaRG cells that overexpressed FOXA3 had hepatocyte-specific functions. RF3 spheroids expressed liver markers following gene and protein expression analysis. After RF3 spheroid transplantation, Fah cKO mice exhibited increased survival, reduced weight loss, normalization of liver function and hepatocyte structure, and enhanced expression of hepatocyte differentiation factors. However, the expression of cell cycle–related proteins, including p53 and p21, was decreased in vivo. Injection of an HNF4α antagonist revealed that inhibition of HNF4α effectively suppressed the regenerative capacity of the liver after RF3 spheroid transplantation, resulting in an increase in the number of p53- and p21-positive cells and a decrease in the expression levels of liver function–related genes.</div></div><div><h3>Conclusions</h3><div>FOXA3 plays an important role in hepatocyte function. RF3 spheroid transplantation had a therapeutic effect in the Fah cKO mouse model, improving liver function and promoting liver regeneration.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101438"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Bile Acids Induce Circadian Rhythm Sleep Disorders in Chronic Liver Diseases","authors":"Lan Zhou ,&nbsp;Min Yan ,&nbsp;Qin Luo ,&nbsp;Wen Qiu ,&nbsp;Yu-Ru Guo ,&nbsp;Xiao-Qing Guo ,&nbsp;Hong-Bin Yu ,&nbsp;Jing-Ru Huo ,&nbsp;Yan-Lin Feng ,&nbsp;De-Ping Wang ,&nbsp;Teng Sun ,&nbsp;Kai-Fang Wang ,&nbsp;Jian-Yun Shi ,&nbsp;Xuan Shang ,&nbsp;Mei-Na Wu ,&nbsp;Lin Wang ,&nbsp;Ji-Min Cao","doi":"10.1016/j.jcmgh.2024.101439","DOIUrl":"10.1016/j.jcmgh.2024.101439","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Sleep disorders (SDs) are common in chronic liver diseases (CLDs). Some SDs arise from impaired internal clock and are, hence, circadian rhythm SDs (CRSDs). Bile acids (BAs), whose levels are increased in many CLDs, reciprocally interact with circadian rhythm. This study explores the mechanisms underlying CRSDs in CLDs and novel therapies.</div></div><div><h3>Methods</h3><div>We monitored the sleep of patients with CLD using actigraphic watch and established male mouse cholemia models by feeding with BA or bile duct ligation. Sleep-wake cycle and circadian rhythm were analyzed by electroencephalogram-electromyography and locomotor wheel-running experiments.</div></div><div><h3>Results</h3><div>Patients with CLD showed CRSD-like phenotypes including increased night activity and early awakening, which were strongly correlated with increased BA levels (ie, cholemia). CRSDs, including shortened circadian period, were recapitulated in 2 cholemic mouse models. Mechanistically, elevated BAs in the suprachiasmatic nucleus (SCN) activated BA receptor Takeda G protein-coupled receptor 5 (Tgr5), which, in turn, increased the level and phosphorylation of Period2 (Per2), a master rhythm regulator, through extracellular signal-regulated kinase (Erk) and casein kinase 1ε (CK1ε). Per2 phosphorylation inhibited its nuclear import, which would release its transcriptional inhibition and expedite the circadian cycle. Cholemia also blunted the light entrainment response and light-induced phase change of SCN mediated by the neurons expressing gastrin releasing peptide through Tgr5-Per2 axis. BA sequestrant or CK1 inhibitor reversed the CRSDs in cholemic mice by restoring Per2 distribution.</div></div><div><h3>Conclusions</h3><div>Cholemia is a major risk factor for CRSDs in CLDs and, hence, a promising target in future clinical study.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101439"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mouse Models for Pancreatic Ductal Adenocarcinoma are Affected by the cre-driver Used to Promote KRASG12D Activation","authors":"Fatemeh Mousavi ,&nbsp;Joyce Thompson ,&nbsp;Justine Lau ,&nbsp;Nur Renollet ,&nbsp;Mickenzie B. Martin ,&nbsp;Jake McGue ,&nbsp;Oneeb Hassan ,&nbsp;Timothy Frankel ,&nbsp;Parisa Shooshtari ,&nbsp;Christopher L. Pin ,&nbsp;Filip Bednar","doi":"10.1016/j.jcmgh.2024.101428","DOIUrl":"10.1016/j.jcmgh.2024.101428","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRAS^G12D). One of the most commonly used models involves targeted insertion of a <em>cre</em>-recombinase into the <em>Ptf1a</em> gene. However, this approach disrupts the <em>Ptf1a</em> gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRAS^G12D). This study aims to determine if <em>Ptf1a</em> haploinsufficiency affected the acinar cell response to KRAS^G12D before and after induction of pancreatic injury.</div></div><div><h3>Methods</h3><div>We performed morphological and molecular analysis of 3 genetically engineered mouse models that express a tamoxifen-inducible <em>cre</em>-recombinase to activate <em>Kras</em>^{<em>G12D</em>} in acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes, <em>Ptf1a</em> or <em>Mist1/Bhlha15</em>, or expressed within a BAC-derived <em>Elastase</em> transgene. Histological and RNA-seq analyses were used to delineate differences between the models.</div></div><div><h3>Results</h3><div>Up to 2 months after tamoxifen induction of KRAS^G12D, morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in <em>Ptf1a</em>^{<em>creERT</em>} pancreata within 7 days and maintained for at least 5 weeks post-injury, which was not seen in the models with 2 functional <em>Ptf1a</em> alleles. RNA-sequencing analysis prior to injury induction suggested <em>Ptf1a</em>^{<em>creERT</em>} and <em>Mist1</em>^{<em>creERT</em>} mice have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the models.</div></div><div><h3>Conclusions</h3><div>These findings suggest <em>Ptf1a</em> haploinsufficiency in <em>Ptf1a</em>^{<em>creERT</em>} mouse models promotes KRAS^G12D priming of genes for promotion of pancreatic ductal adenocarcinoma.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101428"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paneth Cells: Dispensable yet Irreplaceable for the Intestinal Stem Cell Niche","authors":"Michaela Quintero ,&nbsp;Linda C. Samuelson","doi":"10.1016/j.jcmgh.2024.101443","DOIUrl":"10.1016/j.jcmgh.2024.101443","url":null,"abstract":"<div><div>Intestinal stem cells replenish the epithelium throughout life by continuously generating intestinal epithelial cell types, including absorptive enterocytes, and secretory goblet, endocrine, and Paneth cells. This process is orchestrated by a symphony of niche factors required to maintain intestinal stem cells and to direct their proliferation and differentiation. Among the various mature intestinal epithelial cell types, Paneth cells are unique in their location in the stem cell zone, directly adjacent to intestinal stem cells. Although Paneth cells were first described as an epithelial cell component of the innate immune system due to their expression of anti-microbial peptides, they have been proposed to be niche cells due to their close proximity to intestinal stem cells and expression of niche factors. However, function as a niche cell has been debated since mice lacking Paneth cells retain functional stem cells that continue to replenish the intestinal epithelium. In this review, we summarize the intestinal stem cell niche, including the Notch, Wnt, growth factor, mechanical, and metabolic niche, and discuss how Paneth cells might contribute to these various components. We also present a nuanced view of the Paneth cell as a niche cell. Although not required, Paneth cells enhance stem cell function, particularly during intestinal development and regeneration. Furthermore, we suggest that Paneth cell loss induces intestinal stem cell remodeling to adjust their niche demands.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101443"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wall of Resilience: How the Intestinal Epithelium Prevents Inflammatory Onslaught in the Gut","authors":"Eva Liebing ,&nbsp;Susanne M. Krug ,&nbsp;Markus F. Neurath ,&nbsp;Britta Siegmund ,&nbsp;Christoph Becker","doi":"10.1016/j.jcmgh.2024.101423","DOIUrl":"10.1016/j.jcmgh.2024.101423","url":null,"abstract":"<div><div>The intestinal epithelium forms the boundary between the intestinal immune system in the lamina propria and the outside world, the intestinal lumen, which contains a diverse array of microbial and environmental antigens. Composed of specialized cells, this epithelial monolayer has an exceptional turnover rate. Differentiated epithelial cells are released into the intestinal lumen within a few days, at the villus tip, a process that requires strict regulation. Dysfunction of the epithelial barrier increases the intestinal permeability and paves the way for luminal antigens to pass into the intestinal serosa. Stem cells at the bottom of Lieberkühn crypts provide a constant supply of mature epithelial cells. Differentiated intestinal epithelial cells exhibit a diverse array of mechanisms that enable communication with surrounding cells, fortification against microorganisms, and orchestration of nutrient absorption and hormonal balance. Furthermore, tight junctions regulate paracellular permeability properties, and their disruption can lead to an impairment of the intestinal barrier, allowing inflammation to develop or further progress. Intestinal epithelial cells provide a communication platform through which they maintain homeostasis with a spectrum of entities including immune cells, neuronal cells, and connective tissue cells. This homeostasis can be disrupted in disease, such as inflammatory bowel disease. Patients suffering from inflammatory bowel disease show an impaired gut barrier, dysregulated cellular communication, and aberrant proliferation and demise of cells. This review summarizes the individual cellular and molecular mechanisms pivotal for upholding the integrity of the intestinal epithelial barrier and shows how these can be disrupted in diseases, such as inflammatory bowel disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101423"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142513556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKMζ: A Brain Kinase Driving Metabolic Reprogramming and Myofibroblastic Differentiation","authors":"Aveline Filliol","doi":"10.1016/j.jcmgh.2024.101437","DOIUrl":"10.1016/j.jcmgh.2024.101437","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 3","pages":"Article 101437"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and Microbial Analysis of Invasiveness for Escherichia coli Strains Associated With Inflammatory Bowel Disease","authors":"Jungyeon Kim ,&nbsp;Jing Zhang ,&nbsp;Lisa Kinch ,&nbsp;Jinhui Shen ,&nbsp;Sydney Field ,&nbsp;Shahanshah Khan ,&nbsp;Jan-Michael Klapproth ,&nbsp;Kevin J. Forsberg ,&nbsp;Tamia Harris-Tryon ,&nbsp;Kim Orth ,&nbsp;Qian Cong ,&nbsp;Josephine Ni","doi":"10.1016/j.jcmgh.2024.101451","DOIUrl":"10.1016/j.jcmgh.2024.101451","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The adherent-invasive <em>Escherichia coli</em> (AIEC) pathotype is implicated in inflammatory bowel disease (IBD) pathogenesis. AIEC strains are currently defined by phenotypic measurement of their pathogenicity, including invasion of epithelial cells. This broad definition, combined with the genetic diversity of AIEC across patients with IBD, has complicated the identification of virulence determinants. We sought to quantify the invasion phenotype of clinical isolates from patients with IBD and identify the genetic basis for their invasion into epithelial cells.</div></div><div><h3>Methods</h3><div>A pangenome with core and accessory genes (genotype) was assembled using whole genome sequencing of 168 <em>E coli</em> samples isolated from 13 patients with IBD. A modified assay for invasion of epithelial cells (phenotype) was established with consideration of antibiotic resistance phenotypes. Isolate genotype was correlated to invasiveness phenotype to identify genetic factors that cosegregate with invasion.</div></div><div><h3>Results</h3><div>Pangenome-wide comparisons of <em>E coli</em> clinical isolates identified accessory genes that can cosegregate with invasion phenotype. These correlations found the acquisition of antibiotic resistance genes in clinical isolates compromised the traditional gentamicin protection assays used to quantify invasion. Therefore, an alternate assay, based on amikacin resistance, identified genes cosegregating with invasion. These genes encode an arylsulfatase, a glycoside hydrolase, and genetic islands carrying propanediol utilization and sulfoquinovose metabolism pathways.</div></div><div><h3>Conclusions</h3><div>This study highlights the importance of incorporating antibiotic resistance screening for invasion assays used in AIEC identification. Accurately screened invasion phenotypes identified accessory genome elements among <em>E coli</em> IBD isolates that correlate with their ability to invade epithelial cells. These results help explain why single genetic markers for the AIEC phylotype are challenging to identify.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101451"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(24)00212-1","DOIUrl":"10.1016/S2352-345X(24)00212-1","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 2","pages":"Article 101457"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143098663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Multi-organ Male Model of Alcohol-induced Acute-on-chronic Liver Failure Reveals NET-mediated Hepatocellular Death, Which is Prevented by RIPK3 Inhibition","authors":"Martí Ortega-Ribera ,&nbsp;Yuan Zhuang ,&nbsp;Mrigya Babuta ,&nbsp;Veronika Brezani ,&nbsp;Radhika S. Joshi ,&nbsp;Zsuzsanna Zsengeller ,&nbsp;Prashanth Thevkar Nagesh ,&nbsp;Yanbo Wang ,&nbsp;Roderick Bronson ,&nbsp;Gyongyi Szabo","doi":"10.1016/j.jcmgh.2024.101446","DOIUrl":"10.1016/j.jcmgh.2024.101446","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis murine model. Liver, kidney, and brain tissues and behavior were assessed in mice. Livers from patients with sclerosing cholangitis with and without ACLF were also evaluated.</div></div><div><h3>Results</h3><div>In advanced fibrosis induced by BDL, an alcohol binge induced features of ACLF, including significant liver damage, systemic inflammation (increased endotoxin and pro-inflammatory cytokines), and hepatocyte dysfunction compared with BDL alone. ACLF was associated with extrahepatic manifestations, including increased blood urea nitrogen and creatinine, impaired coagulation, and features of encephalopathy. We discovered significantly increased neutrophil count and neutrophil extracellular traps (NETs) in the liver, kidney, and brain in murine ACLF. Livers from ACLF mice showed increased pyroptosis (gasdermin D) and necroptosis (receptor-interacting protein kinase 3 [RIPK3]), when compared with BDL. <em>In vitro</em>, cell-free NETs were induced by alcohol and/or bile acids and triggered pyro-/necroptotic death in hepatocytes. NETosis, pyroptosis, and RIPK3 activation were validated in human livers with ACLF. Moreover, pharmacological inhibition of necroptosis with a RIPK3 inhibitor-ameliorated inflammation, NETs, and liver fibrosis, improving multi-organ ACLF pathophysiology.</div></div><div><h3>Conclusions</h3><div>Our novel ACLF model triggered by alcohol binge mimics key features of pathophysiology and multi-organ impairment in human ACLF. Our results indicate that neutrophil infiltration and NETs contribute to hepatocyte cell death via pyroptosis and necroptosis in ACLF, identifying RIPK3 as a potential therapeutic target.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"19 4","pages":"Article 101446"},"PeriodicalIF":7.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}