Gut最新文献

{"title":"Hypothesis-generating evaluation of multi-armoured oncolytic HSV-1 (VG161) in intrahepatic cholangiocarcinoma: pooled insights from multicentre studies","authors":"Yinan Shen, Xinyan Jin, Wei Song, Tian Fang, Yuwei Li, Zeda Zhao, Xingmei Liang, Qian Tan, Ronghua Zhao, Yuntao Zhang, William Jia, Hongwei Huang, Tengjie Wu, Guoming Shi, Zhewei Zhang, Enliang Li, Guyue Wei, Tao Jiang, Zijun Wang, Zifan Yang, Danni Lin, Linghao Xia, Sida Guo, Jiaxin Li, Fang Wei, Xueyan Shi, Siyuan Chen, Chuntian Tu, Zhanyi Shou, Longshen Xie, Hongchao Zhang, Hangyu Zhou, Peilin Lan, Jun Ding, Wei Chen, Yufu Ye, Xiaozhen Zhang, Yiwen Chen, Xiang Li, Zhenglong Zhai, Wendi Hu, Xiaoyu Zhang, Lei Wang, Xiaoli Sun, Qingwei Zhao, Xingjiang Hu, Youlei Wang, Zhuojun Zhou, Jiejing Kai, Jichen Li, Wei Zhang, Xueli Bai, Tingbo Liang","doi":"10.1136/gutjnl-2025-335904","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-335904","url":null,"abstract":"Background Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with limited treatment options and poor prognosis, especially for patients who failed standard therapies. Objective To explore the safety, efficacy and immunological mechanisms of the novel edition of oncolytic virus vaccination, VG161, a multiarmed oncolytic herpes simplex virus-1 expressing interleukin (IL)-12, IL-15 and a programmed death-ligand 1 antagonist, in patients with advanced ICC. Design This pooled analysis integrates data from two multicentre clinical studies: a Phase I dose-escalation study and a Phase IIa exploratory study. 24 patients with advanced ICC received ultrasound-guided intratumoral injections of VG161. Multiomics analyses were performed on longitudinal tumour biopsies to evaluate immune modulation. Results The oncolytic virus therapy VG161 was well tolerated and showed encouraging antitumour activity, including improved overall survival versus second-line FOLFOX chemotherapy, even though most patients received VG161 as third-line or later therapy. Notably, patients previously treated with immune checkpoint inhibitors (CPIs) experienced enhanced benefit. Multiomics profiling of longitudinal biopsies revealed significant remodelling of the immunosuppressive tumour microenvironment, with proliferated infiltration of antigen-presenting cells, CD8+ T cell activation and M2-like macrophage depletion. Single-cell and spatial transcriptomics identified epithelial and macrophage subpopulations (Epi-C2 and Macro-C1QC) as potential biomarkers of response and resistance. Conclusion These early-phase findings suggest that VG161 elicits meaningful immune activation in ICC and supports further investigation. By inducing both direct oncolysis and multilayered immune activation, VG161 shows clinical benefit in a heavily pretreated population and holds promise for integration with CPI-based regimens. Validation in larger trials is warranted. Data are available in a public, open access repository. Data are available from the corresponding author upon reasonable request.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"26 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145188437","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":"Reply to: ‘Rethinking “inactive chronic hepatitis B”: should we treat patients with high HBsAg levels?’","authors":"Tai-Chung Tseng, Hwai-I Yang, Jia-Horng Kao","doi":"10.1136/gutjnl-2025-336618","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336618","url":null,"abstract":"We appreciate the comments by Chen et al 1 on our recent publication entitled ‘Hepatitis B Surface Antigen Level Identifies Inactive Chronic Hepatitis B Patients from Asia with HCC Risk Below Surveillance Threshold’.2 Their comments highlight the heterogeneity among patients with inactive chronic hepatitis B (CHB) and raise an important clinical question: Should nucleos(t)ide analogue (NA) therapy be initiated in patients with inactive CHB with high hepatitis B surface antigen (HBsAg) levels? First, among the 58 patients with hepatocellular carcinoma (HCC) with baseline HBsAg >100 IU/mL, 27 (46.6%) had hepatitis B virus (HBV) DNA levels <200 IU/mL. Baseline HBV DNA levels were not associated with HCC development in patients with inactive CHB (table 2 of the original article). Given this, we questioned whether viral rebound, rather than baseline viral …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"2 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181129","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":"Gut microbial modulation of 3-hydroxyanthranilic acid and dopaminergic signalling influences attention in obesity","authors":"Anna Castells-Nobau, Andrea Fumagalli, Ángela del Castillo-Izquierdo, Marisel Rosell-Díaz, Lisset de la Vega-Correa, Solveiga Samulėnaitė, Anna Motger-Albertí, María Arnoriaga-Rodríguez, Josep Garre-Olmo, Josep Puig, Rafael Ramos, Aurelijus Burokas, Clàudia Coll, Cristina Zapata-Tona, Vicente Perez-Brocal, Lluis Ramio, Andres Moya, Jonathan Swann, Elena Martín-García, Rafael Maldonado, Jose Manuel Fernández-Real, Jordi Mayneris-Perxachs","doi":"10.1136/gutjnl-2025-336391","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336391","url":null,"abstract":"Background Obesity-related alterations in the gut microbiota have been linked to cognitive decline, yet their relationship with attention remains poorly understood. Objective To evaluate the possible relationships among gut metagenomics, plasma metabolomics and attention. Design We conducted faecal shotgun metagenomics and targeted plasma tryptophan metabolomics across three independent cohorts (n=156, n=124, n=804) with functional validations in preclinical models, including three faecal microbiota transplantation (FMT) experiments in mice and Drosophila melanogaster . Results Obesity was consistently associated with reduced attention. Metagenomics analyses identified Proteobacteria species and microbial functions related to tryptophan biosynthesis from anthranilic acid (AA) as negatively associated with attention in obesity. Plasma tryptophan metabolic profiling and machine learning revealed that 3-hydroxyanthranilic acid (3-HAA) was positively associated with attention, particularly in obesity, while AA showed a negative association. Bariatric surgery improved attention and enriched microbial species linked to attention. In mice, diet-induced obesity (DIO) and microbiota depletion reduced 3-HAA and 5-hydroxy-indole acetic acid (5-HIAA) concentrations in the prefrontal cortex (PFC), which were restored by FMT. Global metabolic profiling (>600 metabolites) of PFC from the FMT group identified 3-HAA and the tryptophan and tyrosine pathways among the most significant in mice receiving microbiota from high-attention donors. A second FMT experiment also revealed a consistent enrichment of the tryptophan and tyrosine metabolism at the transcriptional level in the PFC, with Haao (3-hydroxyantrhanilic acid dioxygenase) and Aox4 (aldehyde oxidase 4), key in 3-HAA and 5-HIAA degradation, among the significantly regulated genes. In a third FMT study, attentional traits were transmitted from humans to mice alongside modulation of serotonergic and dopaminergic pathways. In Drosophila , mono-colonisation with Enterobacter cloacae and DIO induced attention deficit-like behaviours, which were mitigated by 3-HAA supplementation. Conclusions We have identified the microbiota and 3-HAA as potential therapeutic targets to improve attention, especially in obesity. Data are available upon reasonable request. Not applicable.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"22 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181147","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":"Aurora kinase B at the nexus of cholesterol metabolism and therapy response in cholangiocarcinoma","authors":"Elisa Lozano, Javier Vaquero","doi":"10.1136/gutjnl-2025-336445","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336445","url":null,"abstract":"Cholangiocarcinoma (CCA) represents a heterogeneous and highly aggressive group of malignancies arising from the epithelial cells of the biliary tract. Although relatively uncommon, CCA has gained clinical relevance due to its steadily increasing global incidence and mortality. CCA now accounts for approximately 3% of gastrointestinal malignancies, ranking as the second most common hepatobiliary tumour. One of the most significant challenges in managing CCA lies in its typically asymptomatic presentation in early stages, leading to late diagnoses, when surgical resection, the only potentially curative option, is no longer viable.1 The prognosis for patients with CCA remains dismal, with 5-year survival rates below 20%.1 This poor outcome is compounded by the tumour’s genomic, epigenetic and molecular heterogeneity, which limits the efficacy of existing systemic therapies. In particular, the suboptimal performance of current chemotherapy and immunotherapy regimens highlights the urgent need for more effective treatment strategies. This therapeutic gap is largely attributable to an incomplete understanding of the molecular mechanisms driving CCA pathogenesis, underscoring the importance of elucidating its underlying biology to inform rational drug development. In light of the limited efficacy of current treatments, recent attention has shifted towards the role of metabolic reprogramming in tumour progression. In particular, accumulating evidence suggests that deregulated lipid metabolism is a common feature of cancer cells. Cholesterol is an essential component of cell membranes, modulating …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"43 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181133","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":"Reply: Prevalence of serum HBsAg <100 IU/mL in inactive chronic hepatitis B","authors":"Tai-Chung Tseng, Hwai-I Yang, Jia-Horng Kao","doi":"10.1136/gutjnl-2025-336947","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336947","url":null,"abstract":"We appreciate the comments by Fan et al 1 on our recent publication entitled ‘Hepatitis B surface antigen level identifies patients with inactive chronic hepatitis B from Asia with HCC risk below surveillance threshold’.2 They also shared their data from 4386 patients with inactive chronic hepatitis B (CHB), which showed similarities with our findings.1 The authors are particularly interested in the proportion of patients with hepatitis B surface antigen (HBsAg) <100 IU/mL. Among the 2674 patients with inactive CHB from Taiwan, 989 (37.0%) had HBsAg<100 IU/mL, as reported in table 1 of our original article,2 which is close to the 30% …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"9 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181130","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":"Correction: British Society of Gastroenterology guidelines on inflammatory bowel disease in adults: 2025","authors":"BMJ Publishing Group Ltd and British Society of Gastroenterology","doi":"10.1136/gutjnl-2024-334395corr1","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334395corr1","url":null,"abstract":"Moran GW, Gordon M, Sinopoulou V, IBD guideline development group, et al British Society of Gastroenterology guidelines on inflammatory bowel disease in adults: 2025. Gut 2025;74:s1-s101. This …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"15 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140594","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":"Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls.","authors":"Silvana Lobo,Alexandre Dias,Ana Maria Pedro,Marta Ferreira,André Pinto-Oliveira,Celina São José,Jennifer Herrera-Mullar,Nádia Pinto,Chrystelle Colas,Robert Hüneburg,Jacob Nattermann,Lise Boussemart,Liselotte P van Hest,Leticia Moreira,Carolyn Horton,Dana Farengo Clark,Sigrid Tinschert,Lisa Golmard,Isabel Spier,Adriá López-Fernández,Daniela Oliveira,Magali Svrcek,Pierre Bourgoin,Florence Coulet,Hélène Delhomelle,Jeremy Davis,Birthe Zäncker,Conxi Lazaro,Joana Guerra,Maria L Almeida,Sergio Carrera,Ana Patiño,Paul Gundlach,Monika Laszkowska,Vivian E Strong,Manuel R Teixeira,Intan Schrader,Verena Steinke-Lange,Irene Gullo,Sérgio Sousa,Manuela Batista,Stefan Aretz,Judith Balmaña,Melyssa Aronson,Augusto Perazzolo Antoniazzi,Edenir I Palmero,Paul Mansfield,Lizet E van der Kolk,Annemieke Cats,Jolanda M van Dieren,Sergi Castellví-Bel,Bryson Katona,Rachid Karam,Paulo S Pereira,Patrick R Benusiglio,Carla Oliveira","doi":"10.1136/gutjnl-2024-334601","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334601","url":null,"abstract":"BACKGROUNDDiffuse gastric cancer (DGC) is the most common manifestation in germline CTNNA1 variant carriers, with one study estimating a 49-57% lifetime risk by age 80. Knowledge on CTNNA1-associated hereditary diffuse gastric cancer (HDGC), loss-of-function mechanisms, variant-type causality, disease spectrum and cancer risks remains scarce.OBJECTIVEExplore CTNNA1 genotype-phenotype associations to improve genetic testing criteria, surveillance and risk-reduction recommendations for carriers.DESIGNUsing molecular, clinical and population data from 1308 individuals from 351 CTNNA1-variant carrier families and 37 428 non-carriers from European and American ancestries, we analysed genotype-phenotype associations with multivariable logistic regression. With CRISPR/Cas9 CTNNA1-knockout gastric cancer (GC) cells and CTNNA1-humanised Drosophila, we assessed CTNNA1-associated loss-of-function mechanisms.RESULTSCTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin. These transcripts are non-functional in Drosophila, in contrast to non-truncating transcripts. DGC risk is eightfold higher in truncating, compared with non-truncating carriers. The risk of GC and lobular breast cancer (LBC) development in CTNNA1-truncating variant carriers is fivefold and eightfold lower than in CDH1 pathogenic/likely pathogenic variant carriers, respectively. Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers. LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria. Simplification of previous criteria for CTNNA1 genetic testing produced the 'Porto' criteria, which increased CTNNA1-carrier families' pick-up rate by 9%, without performance loss compared with the HDGC 2020 clinical guidelines. Macular dystrophy patterned-2 was positively associated with non-truncating variants, specifically in the αE-catenin M-fragment.CONCLUSIONWe provide compelling evidence supporting that CTNNA1-truncating variants positively associate with DGC and LBC, and NMD as the pathophysiological mechanism leading to CTNNA1 downregulation. We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene. This new knowledge is essential to define surveillance and/or prophylactic measures for CTNNA1-carrier individuals and families.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"38 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140333","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":"Response to: 'Endoscopic intermuscular dissection for rectal cancer: are we ready to skip surgery?' by Ichimasa et al.","authors":"Sander C Albers,Lisa van der Schee,Barbara A J Bastiaansen,Leon M G Moons","doi":"10.1136/gutjnl-2025-336728","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336728","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":"95 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140334","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":"Endoscopic or surgical gastroenterostomy for malignant gastric outlet obstruction: a randomised trial","authors":"Ji Young Bang, Rajesh Puri, Sundeep Lakhtakia, Shyam Thakkar, Irving Waxman, Imran Siddiqui, Kristen Arnold, Adarsh Chaudhary, Shubham Mehta, Amanjeet Singh, Guduru Venkat Rao, Jahangeer Basha, Rajesh Gupta, Shreeyash Modak, Shailendra Singh, Brian Boone, Philip Dautel, Matthew E B Dixon, Hyungjin Myra Kim, Bryce Sutton, Juan Pablo Arnoletti, Thomas Rösch, Shyam Varadarajulu","doi":"10.1136/gutjnl-2025-336339","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336339","url":null,"abstract":"Background Although surgical gastrojejunostomy (SGJ) is the standard method for palliation of gastric outlet obstruction (GOO), an endoscopic method—endoscopic ultrasound-guided gastroenterostomy (EUS-GE)—has been proposed as a novel, less invasive approach. Objective We compared both methods to determine whether clinical outcomes for EUS-GE are superior to surgery. Design We conducted a multicentre, randomised superiority trial of patients with malignant GOO to receive either EUS-GE or SGJ. Primary endpoint was composite measure, consisting of Gastric Outlet Obstruction Scoring System (GOOSS) score of 0 or 1 at hospital discharge, need for reinterventions or supplemental nutrition, or procedure-related adverse events during 6-month follow-up or until death. Secondary endpoints were time to solid diet, length of hospitalisation, health-related quality of life (HRQoL) and treatment costs. Results 74 patients were randomly assigned to EUS-GE (38 patients) or SGJ (36 patients). Primary endpoint occurred in 7.9% of patients who received EUS-GE and 38.9% in SGJ (risk difference −31.0%, 95% CI −47.6% to −11.4%, p=0.002). EUS-GE was associated with more rapid advancement to solid diet (median 2 days (P25–P75, 2–3) vs 5 days (P25–P75, 3.5–9)), shorter hospitalisation (median 3 days (P25–P75, 3–6) vs 9 days (P25–P75, 6–12.5)), better HRQoL for physical (p=0.0016) and social functioning (p=0.011) and lower treatment costs (US$33 934 vs US$51 437, difference −US$17 503 (95% CI −US$27 807 to −US$7920)). Conclusion In this randomised trial, EUS-GE was superior to SGJ with regards to oral intake, need for reinterventions or supplemental nutrition, length of hospitalisation, quality of life and treatment costs. Trial registration number [NCT05548114][1]. Data are available upon reasonable request. All text, tables and figures in this article are available to other researchers. For meta-analysis of individual participant data, individual level de-identified patient data will be available after review and verification. Researchers should contact the corresponding author to request data, providing the corresponding study protocol and the certificate of the institute. These will be verified and approved by the review committee of the trial group, with execution of a data access agreement. All data will be available beginning with publication and ending 12 months after publication. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05548114&atom=%2Fgutjnl%2Fearly%2F2025%2F09%2F24%2Fgutjnl-2025-336339.atom","PeriodicalId":12825,"journal":{"name":"Gut","volume":"13 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133497","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":"Epigenetic therapies in hepatocellular carcinoma: emerging clinical tools and applications.","authors":"Barbara Bueloni,Maite G Fernandez-Barrena,Esteban Fiore,Matias A Avila,Juan Bayo,Guillermo D Mazzolini","doi":"10.1136/gutjnl-2025-336317","DOIUrl":"https://doi.org/10.1136/gutjnl-2025-336317","url":null,"abstract":"Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, largely due to the limited efficacy of current therapies in advanced stages of the disease. Most cases of HCC develop in the setting of chronic liver disease, particularly cirrhosis, where ongoing cycles of inflammation, hepatocyte death and regeneration foster the gradual accumulation of genetic and epigenetic alterations that promote malignant transformation. These molecular changes contribute to the high degree of tumour heterogeneity observed in HCC, a major factor underlying resistance to current treatments. As a result, sustained clinical responses to existing therapies, such as tyrosine kinase inhibitors, anti-angiogenic agents and immune checkpoint inhibitors, remain uncommon. In this context, a growing body of evidence has identified epigenetic dysregulation as a key driver of tumour progression and therapeutic resistance, highlighting a new frontier for intervention. This review provides clinicians and researchers with a comprehensive overview of the emerging field of epigenetic therapies in HCC, summarising results from both completed and ongoing clinical trials involving the so-called 'epidrugs'. Importantly, we discuss how targeting epigenetic mechanisms may not only suppress tumour growth but also enhance the effectiveness of current therapies by reversing resistance pathways. By translating complex molecular insights into tangible therapeutic strategies, epigenetics is poised to reshape the future of HCC management, offering renewed hope for more durable and personalised treatment responses in a disease where progress is urgently needed.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"58 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127180","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}