eGastroenterology最新文献

{"title":"Metabolic dysfunction and alcohol-associated liver disease (MetALD).","authors":"Bin Gao, Juan Pablo Arab, Suthat Liangpunsakul, Wen-Xing Ding, Gyongyi Szabo, Wajahat Mehal, Hua Wang, Yong He, Peter Stärkel, Cristina Llorente, Bernd Schnabl, Seonghwan Hwang, Schalk Vandermerwe, Yanhang Gao, Ming-Hua Zheng, Won Kim, Jacob George, Ramon Bataller, Rohit Loomba, Lorenzo Leggio, Frank Tacke","doi":"10.1136/egastro-2025-100319","DOIUrl":"10.1136/egastro-2025-100319","url":null,"abstract":"<p><p>Metabolic dysfunction and alcohol-associated liver disease (MetALD) is a recently implemented nomenclature and disease terminology for patients with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol. MetALD is diagnosed in individuals who have at least one metabolic risk factor (such as obesity, type 2 diabetes mellitus, hypertension, etc) and consume 140-350 g/week of alcohol for women or 210-420 g/week for men. Conversely, alcohol-associated liver disease is diagnosed in individuals who consume >350 g/week of alcohol for women and >420 g/week for men. MetALD represents a heterogeneous spectrum of liver disease, with variations in clinical presentation and severity driven by differences in metabolic profiles, drinking patterns and individual susceptibility. Alcohol and metabolic risk factors are thought to act synergistically to accelerate steatohepatitis, fibrosis and hepatocellular carcinoma. However, the precise mechanisms underlying liver injury in MetALD still remain poorly understood. In this comprehensive review, we summarise the current definition, diagnostic criteria and clinical management of MetALD. We also discuss emerging insights into understanding its pathogenesis, examine relevant experimental models and highlight future challenges and research priorities in this evolving field.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100319"},"PeriodicalIF":10.5,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12742176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145851851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in postoperative pancreatic fistula: a comprehensive review of predictive factors, therapies, scoring systems and ongoing trials.","authors":"Pasang Sherpa, Fernando F Stancampiano, John A Stauffer, Baoan Ji, Kelvin S Y Shi, Yan Bi","doi":"10.1136/egastro-2025-100232","DOIUrl":"10.1136/egastro-2025-100232","url":null,"abstract":"<p><p>Postoperative pancreatic fistula (POPF) is a critical complication following pancreatic surgeries, marked by leakage of pancreatic fluid due to anastomotic or pancreatic duct failure. Recent advancements have refined its definition, risk classification and management strategies. This review emphasises discussing new definitions, classification updates, predictive factors (both pancreatic and non-pancreatic), comparisons of surgical techniques and therapeutic advancements. Emerging trials and innovations, such as robotic-assisted surgery and personalised stents, are also addressed. The evolving understanding of POPF underscores the need for holistic and patient-centred surgical strategies.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100232"},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12699584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering liver disease models in vitro: emerging trends and innovations.","authors":"Qi Rao, Lei Wang, Frank Tacke, Adrien Guillot, Nan Ma","doi":"10.1136/egastro-2025-100279","DOIUrl":"10.1136/egastro-2025-100279","url":null,"abstract":"<p><p>In vitro liver disease modelling, a rapidly evolving field, has become a multidimensional endeavour aimed at more precisely and effectively recapitulating the complexity of hepatic pathophysiology. This review systematically outlines the essential structural and cellular components of the liver as foundational elements for model design. Emphasising pathophysiological states rather than disease hallmarks, we discuss key liver injury paradigms, including hepatic steatosis, drug-induced hepatotoxicity, fibrogenesis, tumourigenesis and cholestatic injury. Each section integrates cellular mechanisms with model development strategies, highlighting advances in co-culture systems, multicellular organoids and liver-on-a-chip platforms. Although challenges persist, emerging platforms are increasingly capable of capturing multicellular crosstalk, structural heterogeneity and injury-response dynamics. Moving forward, model utility will depend not only on structural mimicry but on the ability to produce biologically meaningful outputs under experimentally controlled conditions.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100279"},"PeriodicalIF":0.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12746833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of SQSTM1/p62 in regulating Mallory-Denk body in alcohol-associated liver disease.","authors":"Kaitlyn Hinz, Hui Qian, Brandon Peiffer, Zhaoli Sun, Hong-Min Ni, Wen-Xing Ding","doi":"10.1136/egastro-2025-100262","DOIUrl":"10.1136/egastro-2025-100262","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-associated liver disease (ALD) is a global health problem without an effective treatment. Mallory-Denk body (MDB) is a protein aggregate commonly found in alcohol-associated hepatitis (AH). MDB primarily contains ubiquitinated proteins, cytokeratin 8 and sequestosome 1 (SQSTM1)/p62. Stress granule (SG) is a cytosolic, membrane-less aggregate composed of various RNA-binding proteins and untranslated mRNA. However, the role and mechanisms of MDB and SG induced by alcohol and their implications in the pathogenesis of ALD remain largely unknown.</p><p><strong>Methods: </strong>SQSTM1/p62 whole body knockout and matched wild-type mice were subjected to the Gao-binge alcohol model or fed a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet alongside Gao-binge alcohol model. ALD mouse liver tissues and human AH liver tissues underwent immunohistochemistry (IHC) staining and western blot analysis for SG and MDB markers.</p><p><strong>Results: </strong>We found that the livers of patients with AH had higher levels of SQSTM1/p62 (MDB marker) and Ras-GTPase-activating protein-binding protein 1 (an SG marker) using IHC staining, and these increased protein levels were enriched in detergent-insoluble fractions compared with healthy individuals. We further discovered that Gao-binge alcohol feeding increased insoluble SG markers, such as phosphorylated eukaryotic initiation factor 2 in mouse livers. Mice fed a DDC diet with Gao-binge alcohol had greater hepatic MDB formation and liver injury than those fed either diet alone. Loss of SQSTM1/p62 led to reduced protein aggregation involved in SGs and MDBs but increased liver injury in DDC plus Gao-binge alcohol-fed mice, indicating that SQSTM1/p62 is required for MDB formation and protects against alcohol-induced liver injury.</p><p><strong>Conclusion: </strong>Chronic plus binge alcohol exposure increases hepatic MDBs and moderate levels of SGs. p62/SQSTM1 is critical for the formation but is not essential for the clearance of MDBs, a process that may act as an adaptive protective mechanism against ALD.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100262"},"PeriodicalIF":0.0,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12612834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145543939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cells in liver metastases: emerging and divergent roles in tumour progression.","authors":"Grace Wu, Ti Yang, Sepideh Gholami, Danielle DePeralta, Matthew Weiss, Meihong Deng, Ping Wang, Hai Huang","doi":"10.1136/egastro-2025-100257","DOIUrl":"10.1136/egastro-2025-100257","url":null,"abstract":"<p><p>Liver metastases (LMs) pose a significant burden of morbidity and mortality, resulting in a worse prognosis for many primary malignancies. Despite advancements in cancer treatment, such as immunotherapy, molecular therapies, additional lines of chemotherapy and optimisation of surgical resection, effective therapy against hepatic metastases remains elusive. Recent studies in immuno-oncology have implicated distinct tumour microenvironment (TME) signatures in the hepatic metastatic niche, which interplay with the intrinsic microenvironmental features specific to each primary tumour or organ of origin. Regulatory T cells (Tregs) have been implicated in the immunosuppressive nature of the hepatic TME, yet the exact mechanisms of interaction have not been fully elucidated. Discrepancies in number, function and proportion of Tregs to other tumour-infiltrating lymphocytes have been documented, with conflicting findings in the LMs from different primary tumours. These results may be attributable to the underlying biology of each organ-specific tumour and the unique hepatic TME that forms during the stepwise progression of the metastatic cascade. In this review, we explore the often-contradicting findings of intrahepatic Tregs in LMs from different originating tumours and offer insight into potential mechanisms for these observed differences with implications for future therapeutic strategies.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100257"},"PeriodicalIF":10.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12593512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver transplantations in Finland over 40 years: evolution and recent trends.","authors":"Fredrik Åberg, Johanna Savikko, Eija Tukiainen, Ville Sallinen, Aki Uutela, Ines Beilmann-Lehtonen, Marko Vannas, Tea Kontio, Arno Nordin","doi":"10.1136/egastro-2025-100219","DOIUrl":"10.1136/egastro-2025-100219","url":null,"abstract":"<p><strong>Background: </strong>Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease, with significant improvements in short-term survival over the decades. However, long-term survival and trends in LT indications and outcomes remain areas of active research. This registry-based study evaluates 40 years of LT in Finland, assessing patient and graft survival, retransplantation rates, changing recipient and donor demographics, indications and benchmarking outcomes against international standards.</p><p><strong>Methods: </strong>Data were extracted from the nationwide Finnish LT registry, covering all LTs performed in Finland between 1982 and 2024. Survival analyses were estimated using the Kaplan-Meier methodology and retransplantation rates were assessed using the cumulative incidence function. Benchmark cases were defined by international criteria.</p><p><strong>Results: </strong>A total of 1763 LTs were performed, with a mean recipient age of 46 years. The most common aetiologies were alcohol-related liver disease (19%) and primary sclerosing cholangitis (PSC; 16%). Over time, recipient and donor age, body mass index and prevalence of diabetes increased. One-year patient survival improved from 83% in the 1980s to 96% in 2020-2024, with the overall 5-year, 10-year, 20-year and 30-year patient survival being 83%, 73%, 53% and 28%, respectively. The retransplantation rate was 13% at 30 years overall and 28% in PSC. Benchmark cases had one-year patient and graft survival rates of 97% and 96%, respectively. Acute rejection rates declined from 62% during 1980-1989 to 19% during 2022-2023. Post-transplant kidney-replacement therapy peaked at 26% in 2010-2021, thereafter decreasing to 8% after the year 2022.</p><p><strong>Conclusion: </strong>The Finnish LT programme demonstrates sustained improvements in short- and mid-term survival, with evolving indications and recipient and donor demographics. Benchmark analyses confirm high-quality outcomes. Continued efforts are needed to optimise long-term survival and reduce the need for retransplantation, especially in PSC.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100219"},"PeriodicalIF":0.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12557772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145395739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy related 14 protects against liver injury by inhibiting multiple cell death pathways.","authors":"Hyeong-Geug Kim, Menghao Huang, Shen Wang, Yang Zhang, Kailing Li, Sheng Liu, Chuanpeng Dong, Xiuxiu Yang, Jung-Hyo Cho, Kushan Chowdhury, Barry Stein, Jun Wan, Xiaocheng Charlie Dong","doi":"10.1136/egastro-2025-100181","DOIUrl":"10.1136/egastro-2025-100181","url":null,"abstract":"<p><strong>Background: </strong>Autophagy is critical for cellular homeostasis. Autophagy related 14 (ATG14) is a key regulator of autophagy initiation; however, its role in hepatocyte survival remains poorly understood. This study aimed to investigate the hepatocyte-specific function of ATG14 <i>in vivo</i>.</p><p><strong>Methods: </strong>We generated <i>Atg14</i> hepatocyte-specific knockout (HepKO) mice using adeno-associated virus to deliver thyroxine-binding globulin gene promoter-driven Cre into <i>Atg14</i> floxed mice at an adult age and fed control and knockout mice with either normal chow or a Western diet. Blood and tissue samples were collected for biochemical and histological analyses.</p><p><strong>Results: </strong><i>Atg14</i> HepKO mice develop severe hepatomegaly under normal dietary conditions. ATG14 deficiency leads to hepatic injury, inflammation and fibrosis. Multiple forms of cell death, including apoptosis and pyroptosis, increase significantly. When challenged with a Western diet for 4 weeks, <i>Atg14</i> HepKO mice exhibit exacerbated hepatic injury, inflammation and fibrosis despite no significant lipid droplet accumulation in the liver. Transcriptomic analysis reveals upregulation of several cell death pathways, including pyroptosis, apoptosis and necroptosis. Further biochemical and microscopic analyses validate the induction of multiple cell death pathways. In addition, NLR family pyrin domain containing 3 inflammasome-mediated pyroptosis is significantly elevated in <i>Atg14</i> HepKO mouse livers and ATG14-deficient hepatocytes.</p><p><strong>Conclusion: </strong>Our data suggest that ATG14 is required for maintaining hepatocyte identity, survival and function and that hepatic ATG14 deficiency may lead to hepatomegaly, tissue injury, inflammation and fibrosis.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100181"},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12542747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145356839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD47: an immunoregulatory nexus in liver and gastrointestinal disorders.","authors":"Josephine Otuagomah, Alana Newcomb, Taesik Gwag, Shuxia Wang","doi":"10.1136/egastro-2025-100242","DOIUrl":"10.1136/egastro-2025-100242","url":null,"abstract":"<p><p>Cluster of differentiation 47 (CD47) is a widely expressed transmembrane protein that serves as a critical immunoregulatory checkpoint in both homeostatic and pathological conditions of the digestive system. It interacts with signal regulatory protein alpha to send a 'do not eat me' signal, thereby preventing phagocytosis and shaping immune responses. Beyond immunity, CD47 also influences cell death, growth and metabolism through interactions with integrins and thrombospondin-1. Recent studies implicate CD47 as a central nexus in the pathogenesis of diverse liver and gastrointestinal disorders, including metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, inflammatory bowel disease, liver ischaemia-reperfusion injury, drug-induced liver injury and gastrointestinal malignancies such as hepatocellular carcinoma, colorectal and pancreatic cancers. CD47 contributes to disease progression through immune modulation, endothelial dysfunction, fibrogenic activation and suppression of antitumour immunity. This review summarises current mechanistic insights into CD47 signalling across digestive diseases and highlights its emerging potential as a therapeutic target for immunometabolic and oncological interventions in gastroenterology and hepatology.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 4","pages":"e100242"},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ursodeoxycholic acid acts as an ileal FXR agonist in male mice with hepatic deficiency of FXR.","authors":"Zakiyah R Henry, Syeda Maliha, Veronia Basaly, Zhenning Yang, Rulaiha E Taylor, Katherine Otersen, Vik Meadows, Daniel Rizzolo, Mary Stofan, Anisha Bhattacharya, Peihong Zhou, Anita Brinker, Ill Yang, Lanjing Zhang, Laurie B Joseph, Brian Buckley, Bo Kong, Grace L Guo","doi":"10.1136/egastro-2025-100227","DOIUrl":"10.1136/egastro-2025-100227","url":null,"abstract":"<p><strong>Background: </strong>Farnesoid X receptor (FXR) has been identified as a therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH). Hepatic FXR is especially critical in suppressing liver inflammation. FXR agonism and antagonism have both proven to be beneficial in the mitigation of MASH, leading to much controversy in the field, particularly regarding FXR signalling in the gut. The objective of this study was to determine the effects of ursodeoxycholic acid (UDCA), a postulated gut FXR antagonist with liver protective effects, on the mitigation and prevention of MASH development in mice with hepatic FXR deficiency.</p><p><strong>Methods: </strong>For this experiment, six-week-old to eight week-old male and female liver-specific FXR knockout (FXR^hep-/-) and control (FXR^{hep flox/flox}) mice were fed either a low-fat control diet (CTL) or a MASH 'Fast Food' diet (Western diet with 21% milk fat, 1.25% cholesterol and 34% sucrose) both supplemented with or without 0.1% (weight/weight; w/w) UDCA for 16 weeks.</p><p><strong>Results: </strong>UDCA feeding tended to reduce alanine aminotransferase levels and decrease liver lipids in the male mice. Supplementation of UDCA showed a trend towards increased UDCA and tauroursodeoxycholic acid (TUDCA) levels in serum, liver and intestine, although the male mice displayed more than twice the amount of these bile acids compared with the female mice. CTL-UDCA feeding resulted in a significant induction of <i>Fxr</i> and <i>Fgf15</i> mRNA expression in the ileum of the male mice.</p><p><strong>Conclusion: </strong>The data strongly suggest that UDCA seems to act as an FXR agonist, especially in the ileum, which contrasts with previous reports that UDCA acts as a gut FXR antagonist. In addition, UDCA seems to be exerting liver protective effects predominantly in the male mice.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 3","pages":"e100227"},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy against colorectal cancer via delivery of anti-PD-L1 nanobody mRNA.","authors":"Wen-Ming Chu, Li Ma, Brian Hew, Atsushi Sugawara, Rodrigo Wengrill, Alex Guarary, Jason S Irei, Owen Chan, Junlong Wang, Hiromi Muramtsu, Woohyun Moon, Nima Sharifai, William Boisvert, Youping Deng, Wei Jia, Norbert Pardi, Pavlos Anastasiadis, Stefan Moisyadi","doi":"10.1136/egastro-2024-100106","DOIUrl":"10.1136/egastro-2024-100106","url":null,"abstract":"<p><strong>Background: </strong>Monoclonal antibodies (mAbs) targeting immune checkpoint molecules such as programmed death ligand 1 (PD-L1), which is expressed in both immune and tumour cells, are conventional immunotherapy approaches. Although approved as monotherapy for the first-line treatment of several cancers, mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer (CRC). Here, we investigated if nucleic acids translated into anti-PD-L1 nanobodies (PDL1Nbs) effectively suppress CRC tumourigenesis in mouse models.</p><p><strong>Methods: </strong>Mice were transplanted with MC-38 mouse sporadic CRC (sCRC) cells or challenged with azoxymethane and dextran sodium sulfate, a combination treatment that induces colitis-associated CRC (CAC). The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA (pDNA) delivered via polymers, or treated with PDL1Nb-encoding nucleoside-modified messenger RNA (PDL1Nb mRNA) delivered via lipid nanoparticles (LNP). Moreover, bone marrow haematopoietic stem cells (BMHSCs) were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide. We examined sCRC tumour proliferation and growth, CAC tumour incidences and numbers, tumour infiltration of immune cells and bone marrow-derived macrophages (BMDMs).</p><p><strong>Results: </strong>Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice. Intriguingly, LNP delivery of the quadruple PDL1Nb (qPDL1Nb) mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb (mPDL1Nb) mRNA in suppressing sCRC tumour progression. Moreover, qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence. Mechanistically, PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages, as well as expression of PD-L1, but increases in tumour-infiltrating CD3⁺CD8⁺ cells during CAC tumourigenesis<i>.</i> Notably<i>, in vitro</i> LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1, CD80, CD86 and CD206 in BMDMs.</p><p><strong>Conclusion: </strong>These results suggest that the PDL1Nb therapy is effective for both CAC and sCRC and using qPDL1Nb mRNA-LNP is a promising alternative strategy for CRC immunotherapy.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 3","pages":"e100106"},"PeriodicalIF":0.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}