Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Escherichia coli Nissle 1917 Modulates the RNF150/ELAVL1 Ubiquitination Pathway to Ameliorate Obesity-driven Insulin Resistance in High-fat Diet-fed Mice.","authors":"Yurou Wang, Yan He, Jiaqi Xie, Jinjun Li, Jianjin Guo","doi":"10.1016/j.jcmgh.2025.101719","DOIUrl":"10.1016/j.jcmgh.2025.101719","url":null,"abstract":"<p><strong>Background & aims: </strong>Obesity, a global epidemic, fuels metabolic dysfunction through complex gut microbiota‒immune system crosstalk. The probiotic Escherichia coli Nissle 1917 (EcN) holds promise for alleviating obesity-related complications, yet its mechanistic underpinnings remain unclear. This study explored the therapeutic potential of EcN, focusing on its ability to regulate the ring finger protein 150 (RNF150)/embryonic lethal abnormal vision-like 1 (ELAVL1) axis in macrophages to counter high-fat diet (HFD)-induced obesity and insulin resistance.</p><p><strong>Methods: </strong>We employed a 12-week dietary intervention in male C57BL/6J mice and administered EcN. Fecal microbiota transplantation (FMT) and myeloid-specific RNF150 and ELAVL1 knockout models were used to establish mechanistic causality. The gut microbiota composition was analyzed via 16S rRNA sequencing, whereas metabolic parameters, adipose tissue inflammation, and RNF150/ELAVL1 interactions were assessed via glucose/insulin tolerance tests, immunohistochemistry, Western blotting, coimmunoprecipitation, and ubiquitination assays. RNF150 expression was also evaluated in adipose tissue and peripheral blood mononuclear cells from overweight and normal-weight human subjects.</p><p><strong>Results: </strong>EcN treatment significantly reduced HFD-induced weight gain, adipose accumulation, and insulin resistance while restoring the gut microbiota balance (decreased the Firmicutes/Bacteroidetes ratio and increased Muribaculaceae). FMT from EcN-treated mice recapitulated these benefits. EcN attenuated inflammation across the liver, adipose, and colon, reducing proinflammatory cytokine levels and macrophage infiltration. RNF150 was upregulated in HFD-fed mice and human overweight samples but downregulated by EcN. Myeloid RNF150 deletion mirrored the effects of EcN, promoting anti-inflammatory M2 macrophages and insulin sensitivity. RNF150 mediated ELAVL1 ubiquitination and degradation, whereas ELAVL1 stabilization enhanced anti-inflammatory responses. Myeloid ELAVL1 deletion worsened metabolic outcomes.</p><p><strong>Conclusions: </strong>EcN ameliorates obesity and insulin resistance by modulating the gut-adipose axis via RNF150/ELAVL1 in macrophages, suggesting novel therapeutic targets for metabolic disorders.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101719"},"PeriodicalIF":7.1,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local Interactions Between Innate Immune Signaling, Microbiota, and Bile Acids Drive the Development of Duodenal Adenomas","authors":"Juan F. Burgueño ,&nbsp;Hajar Hazime ,&nbsp;Julia Fritsch ,&nbsp;Gillian E. Jacobsen ,&nbsp;Henry D. Dione ,&nbsp;Trevor Cickovski ,&nbsp;Eddy E. González ,&nbsp;Ana M. Santander ,&nbsp;Irina Fernández ,&nbsp;Nivis Brito ,&nbsp;Zhen Gao ,&nbsp;Yuguang Ban ,&nbsp;Lily Wang ,&nbsp;Landon Wilson ,&nbsp;Stephen Barnes ,&nbsp;Judith Pignac-Kobinger ,&nbsp;Mark S. Sundrud ,&nbsp;Maria T. Abreu","doi":"10.1016/j.jcmgh.2025.101694","DOIUrl":"10.1016/j.jcmgh.2025.101694","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Duodenal adenomas have malignant potential, yet the drivers of duodenal tumorigenesis remain unclear. Duodenal adenomas robustly develop in villin- Toll-like receptor 4 (TLR4) mice, a transgenic mouse model of increased innate immune signaling in the intestinal epithelium. Here, we sought to test the contributions of the microbiota and bile acids to duodenal adenoma development.</div></div><div><h3>Methods</h3><div>Duodenal tissue was analyzed for proliferation rate and histology in villin-TLR4 vs wild-type mice. Mice were rederived into germ-free conditions and administered a diet containing the bile acid sequestering resin cholestyramine or treated with the NADPH oxidase inhibitor apocynin. Chemokine expression and myeloid cell recruitment were measured. Findings from mouse studies were corroborated by RNA sequencing and tissue microarray analyses of human duodenal adenomas.</div></div><div><h3>Results</h3><div>Constitutive activation of epithelial TLR signaling in the duodenum led to adenomas with an intestinal phenotype. Non-adenomatous duodenal tissue showed increased expression of <em>Cxcl1</em> and <em>Cxcl2</em> by intestinal epithelial cells and recruitment of S100A8⁺ and myeloperoxidase⁺ myeloid cells. Re-deriving villin-TLR4 mice in germ-free conditions or feeding them a cholestyramine-supplemented diet prevented tumor initiation, epithelial expression of CXCR2 ligands, and myeloid cell recruitment. Apocynin supplementation slowed tumor progression without affecting chemokine expression or myeloid cell recruitment. In humans, duodenal adenomas had enriched neutrophil activation pathways, increased chemokine expression, and infiltration of S100A8⁺ and myeloperoxidase⁺ myeloid cells.</div></div><div><h3>Conclusions</h3><div>Bile acids and the microbiota are necessary for duodenal adenoma development and are potentially modifiable risk factors in humans at risk of duodenal adenomas. The recruitment of myeloid cells may promote tumor progression via the release of reactive oxygen species.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101694"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevention of Cholestatic Liver Disease Through BCL6-FXR Enterohepatic Crosstalk","authors":"Ellen Fruzyna ,&nbsp;Meredith A. Sommars ,&nbsp;Yasu Omura ,&nbsp;Kristine M. Yarnoff ,&nbsp;Janice C. Wang ,&nbsp;Christopher R. Futtner ,&nbsp;Richard M. Green ,&nbsp;Grant D. Barish","doi":"10.1016/j.jcmgh.2025.101706","DOIUrl":"10.1016/j.jcmgh.2025.101706","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Bile acid (BA) metabolism must be tightly regulated because BAs serve as metabolic signaling molecules but become cytotoxic at high levels. The farnesoid X receptor (FXR) is a crucial BA sensor, yet our understanding of its regulation and coordination with other transcription factors is limited. Here, we investigated the role of B-cell lymphoma 6 (BCL6) in regulating BA levels and how it coordinates with FXR to protect from BA overload.</div></div><div><h3>Methods</h3><div>We quantified cholesterol, BA levels, expression of key BA regulators, and hepatic damage markers in genetic mouse models with hepatic deletion of <em>Bcl6</em> (<em>Bcl6</em>^<em>LKO</em>), global deletion of <em>Fxr</em> (<em>Fxr</em>^<em>KO</em>), or combined loss of both factors.</div></div><div><h3>Results</h3><div>We identified an epigenomic link between BCL6- and FXR-regulated gene networks. BCL6 regulated BA homeostasis through multiple mechanisms, including suppression of BA synthesis, activation of fibroblast growth factor receptor 4 (FGFR4) expression to sensitize hepatocytes to FGF15-mediated repression of <em>Cyp7a1</em>, and induction of the BA reuptake transporter sodium taurocholate cotransporting polypeptide (NTCP). Combined loss of hepatic <em>Bcl6</em> and whole body <em>Fxr</em> resulted in severe BA accumulation and hepatotoxicity, driven by a near-complete loss of hepatic small heterodimer partner (<em>Shp</em>), indicating that BCL6 and FXR co-repress BA synthesis and maintain BA homeostasis.</div></div><div><h3>Conclusions</h3><div>These findings identify BCL6 as a previously unrecognized integrator of FXR-mediated enterohepatic signaling and a critical regulator of BA metabolism, acting through both FXR-dependent and FXR-independent mechanisms to maintain BA homeostasis and protect the liver from BA-induced injury.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101706"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Metabolism Meets LncRNA Biology: The Role of uc.173 in Intestinal Homeostasis","authors":"Hua Geng,&nbsp;Joann Romano-Keeler,&nbsp;Xiao-Di Tan","doi":"10.1016/j.jcmgh.2025.101662","DOIUrl":"10.1016/j.jcmgh.2025.101662","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101662"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute Phase Response-driven Hepatic Niche Remodeling Promotes Fibrosis Resolution After Alcohol Cessation","authors":"Michael Schonfeld,&nbsp;Kruti Nataraj,&nbsp;Samson Mah,&nbsp;Wei Zhong,&nbsp;Steven A. Weinman,&nbsp;Irina Tikhanovich","doi":"10.1016/j.jcmgh.2025.101689","DOIUrl":"10.1016/j.jcmgh.2025.101689","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Abstinence is beneficial for patients with alcohol-associated liver disease (ALD), but disease resolution after alcohol cessation occurs slowly and only in a subset of patients. We aimed to study the mechanisms of ALD resolution using spatial transcriptomics.</div></div><div><h3>Methods</h3><div>Mice were fed Western diet with 20% alcohol in the drinking water for 20 weeks followed by chow diet with plain water for 4 weeks. Livers were analyzed by 1000-plex CosMx spatial transcriptomics assay (Nanostrings). To assess the role of serum amyloid A (SAA), mice were treated with recombinant SAA or SAA-rich high-density lipoprotein (HDL).</div></div><div><h3>Results</h3><div>Using a mouse model of ALD after alcohol cessation we performed spatial transcriptomics and identified a discrete multicellular fibrogenic and fibrolytic niches. Fibrolytic niches contained a unique subpopulation of hepatocytes that express SAA. SAA expression correlated with fibrolytic genes in mice after alcohol cessation and in human liver samples. In vitro analysis confirmed that <em>Saa1/2</em>^high hepatocytes induced matrix metalloproteinase and lysosomal enzyme (<em>Ctsd, Psap</em>) gene expression in liver macrophages in an SAA and FPR2-dependent way. Moreover, after alcohol cessation, SAA was enriched on circulating HDL and the SAA pro-resolving function required SR-BI-mediated HDL uptake by macrophages. In vivo recombinant SAA or SAA-enriched HDL promoted fibrosis resolution after alcohol cessation in mice. SAA expression itself was mediated by IL-22R signaling in hepatocytes regulated by KDM5B demethylase and C/EBPβ. Hepatocyte-specific <em>Kdm5b</em> or <em>Cebpb</em> knockout promoted <em>Il22a1</em> expression, <em>Saa1/2</em> upregulation and collagen remodeling, facilitating fibrosis resolution after alcohol cessation.</div></div><div><h3>Conclusions</h3><div>Acute phase response activation after alcohol cessation triggers intrahepatic cell-cell communication changes for efficient fibrosis resolution.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101689"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen Signaling in ILC2s Drives Sex Differences in Helicobacter-induced Gastric Inflammation and Atrophy","authors":"Benjamin C. Duncan,&nbsp;Maeve T. Morris,&nbsp;Jordan L. Pascoe,&nbsp;Stuti Khadka,&nbsp;Lei Wang,&nbsp;Gangqing Hu,&nbsp;Jonathan T. Busada","doi":"10.1016/j.jcmgh.2025.101690","DOIUrl":"10.1016/j.jcmgh.2025.101690","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Gastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared with eighth in women. Chronic inflammation driven by <em>Helicobacter pylori</em> infection remains the leading gastric cancer risk factor. Evidence suggests that sex hormones shape sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to <em>Helicobacter</em> infection and contribute to sex disparities in pre-dysplastic disease progression.</div></div><div><h3>Methods</h3><div>Male and female mice were colonized with <em>Helicobacter felis</em>. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using type 2 innate lymphoid cell (ILC2)- and T cell-deficient mouse models.</div></div><div><h3>Results</h3><div>Infected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared with males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, whereas these pathological features were reduced by DHT treatment. Androgen-responsive ILC2s were key initiators of gastric inflammation, and ILC2 depletion abolished the sex differences in <em>H felis</em> pathogenesis.</div></div><div><h3>Conclusions</h3><div>This study reveals that androgens protect from <em>Helicobacter</em>-induced gastric inflammation by modulating ILC2 activation. These findings indicate that ILC2s serve as master regulators of <em>Helicobacter-</em>driven gastric inflammation and highlight their role in directing sex differences in the progression of pre-dysplastic disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101690"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Intestinal Cues Promoting Serotonin Release From the Human Gut","authors":"Sara C. Di Rienzi","doi":"10.1016/j.jcmgh.2025.101664","DOIUrl":"10.1016/j.jcmgh.2025.101664","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101664"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR68, A Proton-sensing GPCR, Mediates Acid-induced Visceral Nociception","authors":"Luke W. Paine ,&nbsp;Rohit Gupta ,&nbsp;James P. Higham ,&nbsp;Javier Aguilera-Lizarraga ,&nbsp;Anne Ritoux ,&nbsp;Thomas Pritchard ,&nbsp;Samuel Nicholson ,&nbsp;James R.F. Hockley ,&nbsp;Tim Raine ,&nbsp;Martin Hausmann ,&nbsp;Kyle Bednar ,&nbsp;Gerhard Rogler ,&nbsp;Fraser Welsh ,&nbsp;Ewan St John Smith ,&nbsp;David C. Bulmer","doi":"10.1016/j.jcmgh.2025.101671","DOIUrl":"10.1016/j.jcmgh.2025.101671","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Localised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as G protein-coupled receptor 68 (GPR68), a proton-sensing G protein-coupled receptor (GPCR) expressed on immune and stromal cells. Single-cell RNA sequencing (RNA-seq) analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception.</div></div><div><h3>Methods</h3><div>Expression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNA-seq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca²⁺ imaging in DRG neurons from wild-type and GPR68^-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist).</div></div><div><h3>Results</h3><div>RNA-seq analysis showed GPR68 is robustly expressed in <em>Trpv1</em>⁺ colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68^-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca²⁺-free buffer, dorsal root ganglion neurons from GPR68^-/- mice or those pretreated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca²⁺ responses. By contrast, the colonic afferent and dorsal root ganglion Ca²⁺ response (in Ca²⁺-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68^-/- mice highlighting the involvement of divergent proton-dependent cellular signaling cascades.</div></div><div><h3>Conclusions</h3><div>These findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101671"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver Sinusoidal Endothelial Cells Promote Metabolic Dysfunction-associated Steatohepatitis Progression via Interleukin-1R1-mediated Chemokine Production Induced by Macrophage-derived Interleukin-1β","authors":"Kenji Fukumoto ,&nbsp;Hayato Hikita ,&nbsp;Yoshinobu Saito ,&nbsp;Yuki Makino ,&nbsp;Kazumasa Soma ,&nbsp;Seiya Kato ,&nbsp;Yoichi Sasaki ,&nbsp;Yuta Myojin ,&nbsp;Katsuhiko Sato ,&nbsp;Sadatsugu Sakane ,&nbsp;Kazuhiro Murai ,&nbsp;Yuki Tahata ,&nbsp;Takahiro Kodama ,&nbsp;Tomohide Tatsumi ,&nbsp;Daisuke Motooka ,&nbsp;Yoshiaki Kubota ,&nbsp;Shogo Kobayashi ,&nbsp;Hidetoshi Eguchi ,&nbsp;Tetsuo Takehara","doi":"10.1016/j.jcmgh.2025.101698","DOIUrl":"10.1016/j.jcmgh.2025.101698","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Interleukin (IL)-1β is a key cytokine in hepatitis-related inflammation, but its role in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) remains unclear. This study investigated IL-1β-mediated interactions in nonparenchymal liver cells to elucidate their contributions to pathological MASH progression.</div></div><div><h3>Methods</h3><div>We used the THP-1 monocyte-derived macrophage line and TMNK-1 liver sinusoidal endothelial cell (LSEC) line for in vitro assays. Endothelial cell-specific Il1r1-knockout (Il1r1^ΔEC) and systemic Cxcl10-knockout (Cxcl10^-/-) mice were subjected to a Western diet (WD) to establish a MASH model. An additional WD-fed cohort received the IL1R1 antagonist anakinra during the final 4 weeks. RNA sequencing data from liver tissues from patients with MASLD and spatial transcriptomic analyses focusing on nontumor regions of MASH-related hepatocellular carcinoma samples were evaluated.</div></div><div><h3>Results</h3><div>Liver levels of mature IL-1β were elevated in WD-fed mice compared with ND-fed mice. Il1r1 was highly expressed in LSECs, and Ccl2 and Cxcl10 expression were upregulated in LSECs under WD conditions. Palmitic acid inhibited autophagy in THP-1 macrophages, increasing IL-1β secretion. IL-1β enhanced CCL2 and CXCL10 expression in TMNK-1 LSECs via JNK activation. In Il1r1^ΔEC and Cxcl10^-/- mice, WD-induced inflammatory cell infiltration and fibrosis were attenuated, and anakinra produced similar effects. In human datasets, CCL2 and CXCL10 were upregulated in MASH livers and correlated with NAFLD activity scores. Spatial transcriptomics revealed a dominant periportal macrophage-to-LSEC IL1B–IL1R1 interaction that generates chemokine-enriched LSECs, forming inflammatory–fibrotic niches that facilitate immune cell recruitment.</div></div><div><h3>Conclusions</h3><div>Macrophage-derived IL-1β promotes hepatic inflammation and fibrosis through IL1R1-dependent chemokine induction in LSECs, highlighting IL1R1 signaling as a therapeutic target in MASH.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101698"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(25)00251-6","DOIUrl":"10.1016/S2352-345X(25)00251-6","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101709"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}