Gut最新文献

{"title":"Patient-level predictors of safety and recurrence after cold versus hot snare resection of large, non-pedunculated colorectal polyps: an individual patient data meta-analysis of four randomised-controlled trials.","authors":"Ingo Steinbrück, Timothy O'Sullivan, Oscar Nogales, Douglas K Rex, Viktor Rempel, Cyrus R Piraka, Oliver Cronin, Sheyla Montori, Christian Wiessner, Thomas Rösch, Eduardo Albéniz, Michael J Bourke, Heiko Pohl","doi":"10.1136/gutjnl-2026-339233","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339233","url":null,"abstract":"<p><strong>Background: </strong>Cold resection is standard for small colorectal polyps and sessile serrated lesions (SSLs). For large (≥20 mm) non-pedunculated adenomas, it appears safer than hot snare endoscopic mucosal resection (EMR) but is associated with higher rates of residual/recurrent adenoma (RRA).</p><p><strong>Objective: </strong>To pool individual patient data from all available randomised controlled trials (RCTs) and determine whether RRA differs across polyp subgroups.</p><p><strong>Design: </strong>International, multicentre post hoc individual patient data meta-analysis of four RCTs. Primary outcomes were rates of major adverse events (AE) (AE=deep mural injury III-V/perforation and/or delayed bleeding) and RRA. Subgroup analyses assessed outcomes by location, size, morphology and histology.</p><p><strong>Results: </strong>1509 polyps in 1423 patients (mean age 66.1 years; mean size 31.3 mm) from 50 centres were included. Major AE occurred in 1.7% of cold versus 5.9% of hot snare resections (OR 0.26; p<0.001). Cold snare was the only factor to reduce major AE in multivariate analysis (OR 0.21; 95% CI 0.07 to 0.60; p=0.004). RRA was higher after cold resection (26.5% vs 12.8%; OR 2.61; p<0.001), with a significant interaction by lesion diameter (p=0.035). By histology, differences were the smallest in SSLs (15.0% vs 8.1%; OR 2.13; p=0.053) and greatest in adenomas with high-grade dysplasia (40.8% vs 18.0%; OR 2.88; p=0.002).</p><p><strong>Conclusions: </strong>Cold resection is safer than hot EMR but results in more than double the RRA in all adenoma subgroups, especially those with high-grade dysplasia. It may be appropriate for SSLs between 2 cm and 4 cm and selected cases under anticoagulant/antiplatelet therapy or multimorbid patients, for which further studies are needed.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976664","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":"International expert panel review for the use of resmetirom and semaglutide in the management of MASH-related fibrosis: clinical practice update","authors":"Maria Mironova,Vlad Ratziu,Mary E Rinella,Meena B Bansal,Mazen Noureddin,Naim Alkhouri,Quentin M Anstee,Philip N Newsome,Jörn M Schattenberg,Arun J Sanyal,Rohit Loomba","doi":"10.1136/gutjnl-2026-340031","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-340031","url":null,"abstract":"The recent conditional US Food and Drug Administration (FDA) approval of two therapies, resmetirom (Rezdiffra) and semaglutide (Wegovy), marks the first time clinicians have pharmacological therapy for metabolic dysfunction-associated steatohepatitis (MASH) with significant fibrosis (F2–F3) without cirrhosis, a disease that previously had no available pharmacological treatment. The two agents act through complementary mechanisms: resmetirom as a liver-directed thyroid hormone receptor-beta agonist and semaglutide as a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a broad spectrum of metabolic effects. In this international expert panel review, we consolidate data from phase III trials, FDA labels and emerging clinical experience into a single resource. It covers the entire care pathway: non-invasive test-based diagnosis of MASH with significant fibrosis, treatment selection and initiation, on-treatment monitoring and response assessment. We offer practical recommendations for individualising therapy by patient phenotype, managing patients already receiving GLP-1 RAs and defining response, non-response and criteria for switching or combining agents. The proposed framework is intended to evolve as long-term outcomes data emerge and additional MASH therapies become available.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"6 1","pages":"gutjnl-2026-340031"},"PeriodicalIF":24.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148933644","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":"Orchestrated cell death pathways in cholangiopathies","authors":"Maria Eugenia Guicciardi,Valeria Pistorio,Pierre-Antoine Soret,Virginie Steunou,Gregory J Gores,Jérémie Gautheron","doi":"10.1136/gutjnl-2026-339264","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339264","url":null,"abstract":"Cholangiopathies comprise a heterogeneous group of chronic liver diseases characterised by progressive bile duct injury, ductular reaction and fibrotic remodelling. Despite distinct aetiologies, these disorders share common cellular stressors that ultimately converge on cholangiocyte dysfunction and loss. In this context, programmed cell death has emerged as a central mechanism linking epithelial stress, immune activation and the development of biliary fibrosis. A range of regulated cell death pathways, including apoptosis, necroptosis, pyroptosis, ferroptosis and autophagy-dependent cell death, can be triggered in cholangiocytes in a disease-dependent and context-dependent manner. Growing evidence suggests that these pathways rarely act in isolation. Instead, they intersect through shared molecular nodes, forming integrated cell death programmes such as PANoptosis. Importantly, it is becoming clear that not only overt cell death but also sublethal activation of death-related signalling can perpetuate cholangiocyte dysfunction and fuel chronic disease progression. Current therapeutic strategies, such as ursodeoxycholic acid and peroxisome proliferator-activated receptor agonists, mainly aim to modify bile composition and improve biochemical parameters. However, they do not directly target the molecular networks governing cholangiocyte death, which may partly explain their limited impact on fibrosis and long-term outcomes. In this review, we synthesise current knowledge on regulated cell death mechanisms in cholangiopathies, highlight key conceptual and technical challenges that complicate their interpretation and therapeutic targeting, and discuss how sublethal death signalling may connect with senescence to sustain cholangiopathy progression and shape therapeutic perspectives.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"27 1","pages":"gutjnl-2026-339264"},"PeriodicalIF":24.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148934222","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":"NCACC maps cross-sample spatial niches and reveals cIgG\u0000 +\u0000 epithelial rare cells driving liver cancer invasion","authors":"Cheng Hai,Yibo Hou,Siyang Yu,Xiaoyu Pan,George Michael Nicolas,Pengcheng Li,Canyucel Gungor,Tianying Yuan,Zhongfu Wang,Zitian Wang,Peter Edward Lobie,Shaohua Ma","doi":"10.1136/gutjnl-2026-338471","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338471","url":null,"abstract":"Background Liver cancer exhibits profound spatial and cellular heterogeneity, contributing to tumour progression, invasion and therapeutic resistance. Emerging evidence suggests that rare low-abundance malignant cell populations residing within discrete tissue niches influence these processes. However, their reliable detection and identification remain challenging due to the limitations of conventional spatial and single-cell transcriptomic analyses, which often rely on single-sample convergence and a lack of cross-cohort reproducibility. Objective To develop a robust framework for identifying rare malignant cell populations across heterogeneous spatial transcriptomic datasets and to characterise their functional role in liver cancer progression. Design We developed the Niche Cluster Atlas with Cellular Co-localisation (NCACC), a dual-layer framework integrating spatial organisation with cellular composition to enable cross-sample niche discovery. NCACC was applied to a comprehensive liver cancer transcriptomic atlas to identify rare niche-associated malignant cell populations. Results NCACC stratified liver cancer tumour architecture into reproducible multicellular niche modules and enabled a tumour-invasive front-enriched rare cancer-derived IgG (cIgG) + epithelial cell population. These cells enhanced proliferative and invasive characteristics and were associated with disease progression. Mechanistic analyses identified a STAT1-dependent cIgG-JAK-STAT signalling axis sustaining the invasive-front phenotype and promoting cIgG + epithelial cell aggressive behaviours. We then combined structure-guided virtual screening with patient-derived organoid validation to identify nordihydroguaiaretic acid and gallic aldehyde as candidate modulators. Conclusion Our study establishes NCACC as a generalisable framework for high-confidence rare malignant cell identification across heterogeneous spatial transcriptomic cohorts, highlighting the cIgG-JAK-STAT as a therapeutically actionable driver of liver cancer invasion.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"4 1","pages":"gutjnl-2026-338471"},"PeriodicalIF":24.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923240","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":"Heterozygous germline mutations in\u0000 MSH3\u0000 , and probably\u0000 MLH3\u0000 , act as classical tumour suppressors, leading to excess somatic deletion mutations, signature ID4 and increased colorectal cancer risk","authors":"Ignacio Soriano,Kitty Sherwood,Joseph C Ward,Juan Fernandez-Tajes,Anusha Amanullah,Steve Thorn,Guler Gul,James F Wilson,Anders Isaksson,Bengt Glimelius,Tobias Sjöblom,Claire Palles,Ian Tomlinson","doi":"10.1136/gutjnl-2026-338390","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338390","url":null,"abstract":"Background MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. Objectives We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. Design About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. Results One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p = 6.6×10 −5  and 1.6-fold, p = 0.028, respectively), owing to somatic ‘second hits’ that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p &lt; 0.0001). CRCs from heterozygotes without ‘second hits’ showed no hypermutation. Conclusion The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2- mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"54 1","pages":"gutjnl-2026-338390"},"PeriodicalIF":24.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923238","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":"From ambition to delivery: why realistic research matters in UK gastroenterology and hepatology","authors":"Vishal C Patel,Debbie L Shawcross,John S Leeds,Lynsey Corless","doi":"10.1136/gutjnl-2026-339954","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339954","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"454 1","pages":"gutjnl-2026-339954"},"PeriodicalIF":24.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923239","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":"Ferroptosis, immune activation and MASH-related HCC.","authors":"Mohammad Shafi Kuchay, Francisco Javier Cubero, Bruno Ramos-Molina","doi":"10.1136/gutjnl-2026-339728","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-339728","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) represents a major global health burden, bridging isolated steatosis, progressive fibrosis and hepatocellular carcinoma. Recent paradigms highlight ferroptosis, an iron-dependent, lipid-peroxidation-driven form of regulated cell death, as a primary lytic initiating event in metabolic liver injury. In this review, we delineate the ferroptosis-immune axis in MASH, characterising it as a self-amplifying, bidirectional circuit. In this framework, parenchymal ferroptotic rupture and damage-associated molecular pattern emission drive myeloid activation and pro-inflammatory cytokine release. This inflammatory microenvironment reciprocally triggers cell-autonomous Kupffer cell ferroptosis and homeostatic collapse. We establish a novel cell-type-specific transcriptomic framework governed by a core four-gene signature (<i>FABP4</i>, <i>CAPG</i>, <i>QSOX1</i> and <i>FXN</i>) that maps the transition from early metabolic stress to advanced structural remodelling. Furthermore, we decode the substrate paradox of polyunsaturated fatty acids, illustrating how their role shifts from physiological signalling to executioner substrates when antioxidant systems collapse. This biophysical vulnerability is heavily primed by inherited gene polymorphisms, including <i>PNPLA3</i>, <i>TM6SF2</i> and <i>MBOAT7</i> By evaluating the sexual dimorphism embedded within these pathways, specifically how the DTL-PROX1 axis dictates distinct iron accumulation rates and lipid peroxidation sensitivities, we propose precise clinical stratification strategies. Finally, we outline actionable translational avenues, highlighting how targeting the ferroptosis-immune axis offers a highly specific therapeutic window to arrest lipotoxicity, suppress inflammation and disrupt oncogenic priming before irreversible tissue remodelling occurs.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929589","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":"Blocking the gut-liver IgA axis attenuates macrophage-mediated inflammation and injury in alcohol-associated liver disease.","authors":"Min Gu Kim, Kwon Yong Tak, Deok Hwa Seo, Gil Won Lee, Sung Woo Cho, Mi Hyun Kwon, Sung Hak Lee, Eui Soo Han, Jae Yong Ryu, Hee Sun Cho, Keung Mo Yang, Ji Won Han, Jeong Won Jang, Ki Young Choi, Pil Soo Sung","doi":"10.1136/gutjnl-2026-338715","DOIUrl":"https://doi.org/10.1136/gutjnl-2026-338715","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-associated liver disease (ALD) is a major cause of morbidity, yet therapies for severe inflammation remain limited.</p><p><strong>Objective: </strong>We examined whether circulating and hepatic immunoglobulin A (IgA) and hepatic myeloid-cell IgA binding are associated with interleukin-1 beta (IL-1β)-linked inflammation and hepatocyte injury in ALD.</p><p><strong>Design: </strong>This single-centre cross-sectional study enrolled consecutive adults with ALD (n=276), chronic hepatitis B (CHB; n=177) and healthy controls (n=20). A clinically indicated liver-biopsy subcohort underwent flow cytometry, immunohistochemistry and real-time quantitative PCR. Mice received 16-day chronic-plus-binge ethanol feeding±fingolimod (FTY720; 1 mg/kg/day). CD14⁺ monocytes were stimulated on plate-bound secretory IgA (sIgA)±lipopolysaccharide (LPS) and conditioned media were applied to Huh7 cells.</p><p><strong>Results: </strong>Serum IgA was higher in ALD (median 323-412 mg/dL) than in healthy/CHB (194/211 mg/dL; p<0.001) and correlated with hepatic IgA+area (ρ=0.680, p<0.001). Serum IgA correlated with CD68-normalised IL1B transcripts (ρ=0.383, p=0.008), while hepatic CD14⁺ cells from ALD samples showed greater IgA binding than those from CHB samples (p<0.05). In mice, serum IgA correlated with IgA-bound macrophage frequency (n=16, ρ=0.844, p<0.001). FTY720 reduced serum IgA (p<0.01), IgA-bound macrophages (p<0.001) and <i>Cd68</i>-normalised <i>Il1b</i> transcripts (p<0.01), and attenuated ethanol-induced liver injury (alanine aminotransferase/aspartate aminotransferase; p<0.05). Spatial transcriptomics suggested attenuation in monocyte-derived macrophage-enriched regions and IL-1-linked programmes with FTY720. sIgA+LPS monocyte supernatants contained higher tumour necrosis factor-α/IL-1β than LPS alone (Δ+280/+798 pg/mL, p<0.01) and increased Huh7-cell apoptosis (Δ+2.96% p; p<0.01).</p><p><strong>Conclusion: </strong>IgA binding to hepatic myeloid cells is associated with interleukin (IL)-1-linked inflammation in ALD, and in ethanol-fed mice pharmacologic modulation of immune-cell trafficking was accompanied by reduced IgA-bound hepatic myeloid cells and attenuated IL-1-related inflammation.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":24.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905964","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":"Rome V global epidemiology and validation survey: prevalence of disorders of gut-brain interaction and comparison with the Rome IV global epidemiology study.","authors":"Ami D Sperber, Johann P Hreinsson, Magnus Simrén, Douglas A Drossman, Viola Andresen, Serhat Bor, Dan L Dumitrascu, Xiucai Fang, Guijun Fei, Luis Bustos Fernandez, Carlos Francesconi, Shin Fukudo, Sang Kil Lee, Chloé Melchior, Agata Mulak, Anne F Peery, David M Rodrigues, Javier Santos, Max Schmulson, Dipesh H Vasant, Jan Tack, Tiffany Taft, Olafur S Palsson","doi":"10.1136/gutjnl-2026-339666","DOIUrl":"10.1136/gutjnl-2026-339666","url":null,"abstract":"<p><strong>Background: </strong>The recently published Rome V adult diagnostic criteria facilitated an updated epidemiological survey of disorders of gut-brain interaction (DGBI).</p><p><strong>Objective: </strong>We aimed to describe the global epidemiology of DGBI using the Rome V criteria and compare it with the Rome IV Rome Foundation Global Epidemiology Study.</p><p><strong>Methods: </strong>A population-based Internet survey of 28,771 adults was conducted in 15 countries using the Rome V diagnostic questionnaire. DGBI prevalence was determined and compared with the Rome IV data. Multivariable logistic regression models were used to examine associations of demographic factors to Rome V DGBI status in the global population and to assess potentially associated clinical factors.</p><p><strong>Results: </strong>The surveys yielded similar results. The prevalence of at least one DGBI using the Rome V criteria was 40.9%, compared with 40.5% for Rome IV. In both, the prevalence was higher among females and decreased with increasing age. In the Rome V sample (25 DGBI), the most prevalent oesophageal disorder was functional dysphagia at 4.1%, the most prevalent gastroduodenal disorder was functional dyspepsia at 8.1%, unclassified bowel disorder was the most prevalent bowel disorder (9.6%), followed by chronic constipation (8.9%) and IBS (8.5%) and proctalgia fugax was the most prevalent anorectal disorder (7.3%). The prevalence rates for two new DGBI were 5.1% for abdominal migraine and 1.4% for inability to belch syndrome.</p><p><strong>Conclusion: </strong>The Rome V global prevalence of DGBI is consistent with Rome IV. This bolsters confidence in the validity of prevalence rates for DGBI and reaffirms their high global burden.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1887-1897"},"PeriodicalIF":24.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792193","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":"Trogocytosis-orchestrated CLDN18.2-\"dressed\" CD8⁺ T cells drive pancreatic cancer progression via glucose metabolic reprogramming-induced cytotoxicity debilitation and systematic immune senescence cascade.","authors":"Tianxing Zhou, Jingrui Yan, Yu Zhang, Guohua Mao, Tinghai Hu, Shangheng Shi, Fanyue Shao, Jingbo Xu, Yaqi Zhang, Yifei Wang, Zekun Li, Hongwei Wang, Song Gao, Tiansuo Zhao, Antao Chang, Chongbiao Huang, Jun Yu, Yukuan Feng, Xiuchao Wang, Yongjie Xie, Bin Wang, Chao Yang, Jihui Hao","doi":"10.1136/gutjnl-2025-335790","DOIUrl":"10.1136/gutjnl-2025-335790","url":null,"abstract":"<p><strong>Background: </strong>As it is a tumour-associated antigen in epithelial cells, research on claudin18.2 (CLDN18.2) has focused on its role as a therapeutic target in pancreatic cancers and its part in maintaining tight junctions.</p><p><strong>Objective: </strong>We elucidate the role of trogocytosis-related CLDN18.2 in CD8⁺ T cells and pancreatic ductal adenocarcinoma (PDAC) progression.</p><p><strong>Design: </strong>We constructed humanised hCD34⁺, Trp53^R172HKras^G12DPdx1-cre (KPC), Cldn18.2 knockout (KO), and patient-derived xenograft/organoid mouse models. Flow cytometry, immunofluorescence, single-cell RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed.</p><p><strong>Results: </strong>CLDN18.2⁺CD8⁺ T cells indicated poor pancreatic cancer prognosis and immunotherapeutic resistance. CD8⁺ T cells acquired CLDN18.2 from tumour cells via trogocytosis, inhibiting their activation and cytotoxicity. \"Dressed\" CLDN18.2 suppressed glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8⁺ T cells. Mechanically, trogocytosis-related CLDN18.2 induced GSK3β/CK1α-mediated β-catenin phosphorylation, promoting β-catenin ubiquitination and proteasome degradation in CD8⁺ T cells. CLDN18.2 interacted with β-catenin's N-terminal domain via its C-terminal domain, further strengthening the interaction between β-catenin and CK1α. Moreover, CLDN18.2⁺CD8⁺ T cells preferentially 'homed' to the bone marrow through the CXCL12/CXCR4 axis, skewed haematopoietic stem cell myeloid differentiation and induced systemic immune senescence via IL1α. Notably, preclinical mouse studies showed PC18.1 peptide sensitised immunotherapy and suppressed PDAC progression by disrupting the CLDN18.2/β-catenin interaction in CD8⁺ T cells.</p><p><strong>Conclusions: </strong>Trogocytosis-related CLDN18.2 inhibited the glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8⁺ T cells by promoting the ubiquitin-proteasomal degradation of β-catenin in PDAC. Therefore, targeting trogocytosis-related CLDN18.2⁺CD8⁺ T cells may be a promising therapeutic strategy to inhibit PDAC progression.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1983-1999"},"PeriodicalIF":24.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146156781","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}