Pub Date : 2026-02-04DOI: 10.1097/hep.0000000000001692
Kristel K. Leung, Wenbin Li, Bettina Hansen, Aliya Gulamhusein, Lauren Lapointe-Shaw, Amanda Ricciuto, Eric I. Benchimol, Jennifer A. Flemming, Gideon M. Hirschfield
Background & Aims: Primary sclerosing cholangitis (PSC) is a pre-malignant condition with elevated risk of hepatopancreatobiliary cancers (HPBCa) and colorectal cancer (CRC) when inflammatory bowel disease (IBD) is present. We described cancer burden in a contemporary PSC-IBD cohort, and assessed rates of subsequent cancers, liver transplant and death post-colectomy or post-cholecystectomy status. Methods: Using linked health administrative databases, we calculated cause-specific cumulative incidences of HPBCa-related outcomes (diagnoses/deaths) and non-HPBCa-related transplant/death among individuals with PSC-IBD in Ontario, Canada (2002–2018) followed to 2021. Transition probabilities and transition intensity ratios (TIR) were evaluated using a multistate Markov model. Results: Amongst 476 individuals with incident PSC-IBD, there was a 54% probability of remaining event-free at 10 years, while approximately 1 in 20 experienced an HPBCa-related outcome, and up to 1 in 4 had a non-HPBCa-related transplant/death. During follow-up, 13% experienced multiple events. Age was associated with HPBCa (HR 1.02, 95% CI 1.01–1.04), but not male sex. Mortality occurred more frequently post-colectomy (TIR 3.08, 95% CI 1.7-5.59) and post-cholecystectomy (TIR 3.85, 95% CI 2.21-6.64) relative to event-free PSC-IBD, but there were no differences in post-surgery incidence of cancer or transplant. Conclusions: While some individuals with PSC-IBD experience an extended event-free disease course, a large proportion experienced disease-related cancer, colectomy, cholecystectomy and transplant events. Higher mortality rates observed after surgery are likely related to underlying disease processes that motivated surgical intervention (e.g. dysplasia/malignancy, refractory IBD), rather than the surgery itself. Understanding how PSC-IBD disease trajectories vary can inform individual management and patient counselling.
背景和目的：原发性硬化性胆管炎（PSC）是一种恶性前病变，当存在炎症性肠病（IBD）时，其发生肝胰胆管癌（HPBCa）和结直肠癌（CRC）的风险升高。我们描述了当代PSC-IBD队列的癌症负担，并评估了随后的癌症、肝移植和结肠切除术或胆囊切除术后死亡的发生率。方法：使用相关的卫生管理数据库，我们计算了加拿大安大略省PSC-IBD患者（2002-2018年）中hpbca相关结局（诊断/死亡）和非hpbca相关移植/死亡的病因特异性累积发生率。利用多态马尔可夫模型对过渡概率和过渡强度比进行了评估。结果：在476例PSC-IBD患者中，在10年内无事件发生的概率为54%，而大约1 / 20的患者经历了与hpbca相关的结果，高达1 / 4的患者发生了与hpbca无关的移植/死亡。在随访期间，13%的人经历了多重事件。年龄与HPBCa相关（HR 1.02, 95% CI 1.01-1.04），但与男性无关。与无事件的PSC-IBD相比，结肠切除术后（TIR 3.08, 95% CI 1.7-5.59）和胆囊切除术后（TIR 3.85, 95% CI 2.21-6.64）的死亡率更高，但术后癌症或移植的发生率无差异。结论：虽然一些PSC-IBD患者经历了较长的无事件病程，但很大比例的患者经历了与疾病相关的癌症、结肠切除术、胆囊切除术和移植事件。术后观察到的较高死亡率可能与引起手术干预的潜在疾病过程有关（如发育不良/恶性肿瘤，难治性IBD），而不是手术本身。了解PSC-IBD疾病轨迹的变化可以为个体管理和患者咨询提供信息。
{"title":"Understanding hepatopancreatobiliary cancer risks in a population-based primary sclerosing cholangitis-inflammatory bowel disease cohort","authors":"Kristel K. Leung, Wenbin Li, Bettina Hansen, Aliya Gulamhusein, Lauren Lapointe-Shaw, Amanda Ricciuto, Eric I. Benchimol, Jennifer A. Flemming, Gideon M. Hirschfield","doi":"10.1097/hep.0000000000001692","DOIUrl":"https://doi.org/10.1097/hep.0000000000001692","url":null,"abstract":"Background & Aims: Primary sclerosing cholangitis (PSC) is a pre-malignant condition with elevated risk of hepatopancreatobiliary cancers (HPBCa) and colorectal cancer (CRC) when inflammatory bowel disease (IBD) is present. We described cancer burden in a contemporary PSC-IBD cohort, and assessed rates of subsequent cancers, liver transplant and death post-colectomy or post-cholecystectomy status. Methods: Using linked health administrative databases, we calculated cause-specific cumulative incidences of HPBCa-related outcomes (diagnoses/deaths) and non-HPBCa-related transplant/death among individuals with PSC-IBD in Ontario, Canada (2002–2018) followed to 2021. Transition probabilities and transition intensity ratios (TIR) were evaluated using a multistate Markov model. Results: Amongst 476 individuals with incident PSC-IBD, there was a 54% probability of remaining event-free at 10 years, while approximately 1 in 20 experienced an HPBCa-related outcome, and up to 1 in 4 had a non-HPBCa-related transplant/death. During follow-up, 13% experienced multiple events. Age was associated with HPBCa (HR 1.02, 95% CI 1.01–1.04), but not male sex. Mortality occurred more frequently post-colectomy (TIR 3.08, 95% CI 1.7-5.59) and post-cholecystectomy (TIR 3.85, 95% CI 2.21-6.64) relative to event-free PSC-IBD, but there were no differences in post-surgery incidence of cancer or transplant. Conclusions: While some individuals with PSC-IBD experience an extended event-free disease course, a large proportion experienced disease-related cancer, colectomy, cholecystectomy and transplant events. Higher mortality rates observed after surgery are likely related to underlying disease processes that motivated surgical intervention (e.g. dysplasia/malignancy, refractory IBD), rather than the surgery itself. Understanding how PSC-IBD disease trajectories vary can inform individual management and patient counselling.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"92 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115863","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}
Pub Date : 2026-02-03DOI: 10.1097/hep.0000000000001705
Julie Lucifora, Francesco Negro
{"title":"Shedding new light on the chicken-and-egg dilemma of Hepa55s Delta Virus (HDV) replica5on ini5a5on","authors":"Julie Lucifora, Francesco Negro","doi":"10.1097/hep.0000000000001705","DOIUrl":"https://doi.org/10.1097/hep.0000000000001705","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"6 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110006","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}
Background & Aims: Metabolic-dysfunction-associated steatotic liver disease (MASLD), including its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), is increasingly recognized as a critical global health challenge. This study investigates the role of hepatic GPR75 in MASH progression. Approach & Results: Although GPR75 is not abundantly expressed in the liver in healthy individuals, its protein levels significantly increase during MASH. Depletion of Gpr75 in either the whole liver or specifically in hepatocytes protected mice from diet-induced hepatic steatosis, while hepatocyte-specific overexpression of Gpr75 exacerbated diet-induced MASH and liver fibrosis. The deficiency of hepatic Gpr75 activated the GNAI2-cAMP-PKA signaling pathway in the livers of MASLD mice, reducing SREBP-1c maturation and de novo lipogenesis. Mechanistically, VPS35 stabilized GPR75 by recycling it to the hepatocyte membrane, thereby decreasing its degradation during MASH progression. Conclusions: This study demonstrates that GPR75 serves as a novel regulator of MASLD /MASH by modulating hepatic fatty acid metabolism. These findings suggest that GPR75 suppression may represent a potential therapeutic strategy for MASLD/MASH treatment.
{"title":"Hepatic GPR75 exacerbates MASH through GNAI2-Dependent signaling","authors":"Xule Yang, Na Yang, Zhihao Cheng, Rui Zhang, Hui Fan, Dongsheng Liu, Jiye Aa, Guangji Wang, Yuan Xie","doi":"10.1097/hep.0000000000001706","DOIUrl":"https://doi.org/10.1097/hep.0000000000001706","url":null,"abstract":"Background & Aims: Metabolic-dysfunction-associated steatotic liver disease (MASLD), including its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), is increasingly recognized as a critical global health challenge. This study investigates the role of hepatic GPR75 in MASH progression. Approach & Results: Although GPR75 is not abundantly expressed in the liver in healthy individuals, its protein levels significantly increase during MASH. Depletion of <jats:italic toggle=\"yes\">Gpr75</jats:italic> in either the whole liver or specifically in hepatocytes protected mice from diet-induced hepatic steatosis, while hepatocyte-specific overexpression of <jats:italic toggle=\"yes\">Gpr75</jats:italic> exacerbated diet-induced MASH and liver fibrosis. The deficiency of hepatic <jats:italic toggle=\"yes\">Gpr75</jats:italic> activated the GNAI2-cAMP-PKA signaling pathway in the livers of MASLD mice, reducing SREBP-1c maturation and de novo lipogenesis. Mechanistically, VPS35 stabilized GPR75 by recycling it to the hepatocyte membrane, thereby decreasing its degradation during MASH progression. Conclusions: This study demonstrates that GPR75 serves as a novel regulator of MASLD /MASH by modulating hepatic fatty acid metabolism. These findings suggest that GPR75 suppression may represent a potential therapeutic strategy for MASLD/MASH treatment.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"8 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110009","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}
Background and Aims: Liver fibrosis poses a major health threat globally, with an acute shortage of effective treatments to stop or reverse its progression. Hepatocyte injury serves as the primary cause of liver fibrosis, and restoring the expression of damaged proteins via mRNA delivery represents a promising therapeutic strategy. Clinical studies and animal models have demonstrated that mitochondrial ornithine transcarbamylase ( OTC ) deficiency correlates with increased incidence to liver fibrosis. In this study, we examined the therapeutic potential of OTC mRNA delivery of liver fibrosis. Approach and Results: Analysis of OTC expression and distribution in liver fibrosis revealed significant downregulation in fibrotic tissues. Restoring OTC expression in hepatocytes through AAV8-TBG-OTC significantly inhibits the progression of liver fibrosis. OTC mRNA sequences were developed using a codon-optimization artificial intelligence (AI) tool and synthesized with N1-methylpseudouridine modification followed by encapsulation into lipid nanoparticle (LNP). Repeated in vivo delivery of OTC mRNA-LNP induced a robust inhibition of fibrogenesis in multiple mouse liver fibrosis models. Mechanistically, restoring OTC mRNA expression significantly recovers impaired mitochondrial and hepatocyte functions, while concurrently inhibiting paracrine ammonia-induced activation of HSCs and macrophages. OTC mRNA significantly suppresses collagen deposition, while the THR- β agonist Resmetirom potently inhibits lipid accumulation; the combination exhibits potent complementary efficacy against metabolic dysfunction-associated steatohepatitis (MASH) liver fibrosis. Conclusion: Collectively, our study provides the first direct preclinical evidence supporting OTC mRNA therapeutics for treating liver fibrosis and establishes proof-of-concept for mRNA therapy as a novel strategy to reverse liver fibrosis.
{"title":"Lipid nanoparticle-delivered ornithine transcarbamylase mRNA alleviates liver fibrosis in preclinical models","authors":"Dongqing Zhai, Jiaping Ni, Xianyu Shao, Weijun Zhao, Yuenan Chen, Kailin Fan, Jingtong Li, Yumeng Shen, Ang Lin, Weiwei Hu, Yong Yang","doi":"10.1097/hep.0000000000001708","DOIUrl":"https://doi.org/10.1097/hep.0000000000001708","url":null,"abstract":"Background and Aims: Liver fibrosis poses a major health threat globally, with an acute shortage of effective treatments to stop or reverse its progression. Hepatocyte injury serves as the primary cause of liver fibrosis, and restoring the expression of damaged proteins via mRNA delivery represents a promising therapeutic strategy. Clinical studies and animal models have demonstrated that mitochondrial ornithine transcarbamylase ( <jats:italic toggle=\"yes\">OTC</jats:italic> ) deficiency correlates with increased incidence to liver fibrosis. In this study, we examined the therapeutic potential of <jats:italic toggle=\"yes\">OTC</jats:italic> mRNA delivery of liver fibrosis. Approach and Results: Analysis of OTC expression and distribution in liver fibrosis revealed significant downregulation in fibrotic tissues. Restoring OTC expression in hepatocytes through AAV8-TBG-OTC significantly inhibits the progression of liver fibrosis. <jats:italic toggle=\"yes\">OTC</jats:italic> mRNA sequences were developed using a codon-optimization artificial intelligence (AI) tool and synthesized with N1-methylpseudouridine modification followed by encapsulation into lipid nanoparticle (LNP). Repeated <jats:italic toggle=\"yes\">in vivo</jats:italic> delivery of <jats:italic toggle=\"yes\">OTC</jats:italic> mRNA-LNP induced a robust inhibition of fibrogenesis in multiple mouse liver fibrosis models. Mechanistically, restoring <jats:italic toggle=\"yes\">OTC</jats:italic> mRNA expression significantly recovers impaired mitochondrial and hepatocyte functions, while concurrently inhibiting paracrine ammonia-induced activation of HSCs and macrophages. <jats:italic toggle=\"yes\">OTC</jats:italic> mRNA significantly suppresses collagen deposition, while the THR- <jats:italic toggle=\"yes\">β</jats:italic> agonist Resmetirom potently inhibits lipid accumulation; the combination exhibits potent complementary efficacy against metabolic dysfunction-associated steatohepatitis (MASH) liver fibrosis. Conclusion: Collectively, our study provides the first direct preclinical evidence supporting <jats:italic toggle=\"yes\">OTC</jats:italic> mRNA therapeutics for treating liver fibrosis and establishes proof-of-concept for mRNA therapy as a novel strategy to reverse liver fibrosis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"31 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146110007","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}
Pub Date : 2026-02-02DOI: 10.1097/hep.0000000000001699
Younghun Han, Jinyoung Byun, Caitlin J. VanLith, Matthew A. Cooley, Vikram R. Shaw, Rikita I. Hatia, Fowsiyo Y. Ahmed, Nasra H. Giama, Hawa M. Ali, Nellie A. Campbell, Mohamed Hassan, Jesper B. Andersen, Victor Ankoma-Sey, Jesus M. Banales, Luis Bujanda, Oliver F. Bathe, Tanios S. Bekaii-Saab, Mitesh J. Borad, Niklas K. Björkström, Carlos H. F. Chan, Sean P. Cleary, Martin Cornillet, Trine Folseraas, Peter R. Galle, Jeanine M. Genkinger, Robert J. MacInnis, Gregory J. Gores, Lipika Goyal, Richard S. Houlston, Sumera I. Ilyas, Milind Javle, Julia S. Johansen, Troels D. Christensen, Ashwin S. Kamath, Robin Kate Kelley, Shahid A. Khan, Richard D. Kim, Sandi A. Kwee, Angela Lamarca, Frank Lammert, Nicholas F. LaRusso, Stacie Lindsey, Rocio I. R. Macias, Harmeet Malhi, Tushar C. Patel, Jennifer B. Permuth, Helen L. Reeves, Stephen Rossi, William Sanchez, Rory L. Smoot, Anthony J. Swerdlow, Hop S. Tran Cao, Juan W. Valle, Arndt Weinmann, Julia Weinmann-Menke, Linda L. Wong, Xuehong Zhang, Vincent Zimmer, Andrew X. Zhu, Konstantinos N. Lazaridis, Brian D. Juran, Prasun Jalal, Jennifer J. Knox, Amy Hutchinson, Belynda Hicks, Jill E. Koshiol, Stephen J. Chanock, Manal M. Hassan, Christopher I. Amos, Katherine A. McGlynn, Lewis R. Roberts
Background & Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach & Results: We conducted a GWAS of 2,366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( P <5×10 -8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified one new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and two variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for twelve traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.
{"title":"Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses","authors":"Younghun Han, Jinyoung Byun, Caitlin J. VanLith, Matthew A. Cooley, Vikram R. Shaw, Rikita I. Hatia, Fowsiyo Y. Ahmed, Nasra H. Giama, Hawa M. Ali, Nellie A. Campbell, Mohamed Hassan, Jesper B. Andersen, Victor Ankoma-Sey, Jesus M. Banales, Luis Bujanda, Oliver F. Bathe, Tanios S. Bekaii-Saab, Mitesh J. Borad, Niklas K. Björkström, Carlos H. F. Chan, Sean P. Cleary, Martin Cornillet, Trine Folseraas, Peter R. Galle, Jeanine M. Genkinger, Robert J. MacInnis, Gregory J. Gores, Lipika Goyal, Richard S. Houlston, Sumera I. Ilyas, Milind Javle, Julia S. Johansen, Troels D. Christensen, Ashwin S. Kamath, Robin Kate Kelley, Shahid A. Khan, Richard D. Kim, Sandi A. Kwee, Angela Lamarca, Frank Lammert, Nicholas F. LaRusso, Stacie Lindsey, Rocio I. R. Macias, Harmeet Malhi, Tushar C. Patel, Jennifer B. Permuth, Helen L. Reeves, Stephen Rossi, William Sanchez, Rory L. Smoot, Anthony J. Swerdlow, Hop S. Tran Cao, Juan W. Valle, Arndt Weinmann, Julia Weinmann-Menke, Linda L. Wong, Xuehong Zhang, Vincent Zimmer, Andrew X. Zhu, Konstantinos N. Lazaridis, Brian D. Juran, Prasun Jalal, Jennifer J. Knox, Amy Hutchinson, Belynda Hicks, Jill E. Koshiol, Stephen J. Chanock, Manal M. Hassan, Christopher I. Amos, Katherine A. McGlynn, Lewis R. Roberts","doi":"10.1097/hep.0000000000001699","DOIUrl":"https://doi.org/10.1097/hep.0000000000001699","url":null,"abstract":"Background & Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach & Results: We conducted a GWAS of 2,366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( <jats:italic toggle=\"yes\">P</jats:italic> <5×10 <jats:sup>-8</jats:sup> ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified one new genome-wide significant variant, rs535777 (OR=1.44), near <jats:italic toggle=\"yes\">HLA-DRB1/DQA1</jats:italic> associated with CCA, and two variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in <jats:italic toggle=\"yes\">LINC02506</jats:italic> at 4p15.1 and rs6914950 (OR=1.63) near <jats:italic toggle=\"yes\">HLA-DRB1/DQB1</jats:italic> . Stratified analyses revealed rs2395184 (OR=3.51) near <jats:italic toggle=\"yes\">HLA-DRA/DRB5</jats:italic> associated with PSC-related CCA, and rs142674434 (OR=2.98) in <jats:italic toggle=\"yes\">THSD7A</jats:italic> at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for twelve traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"67 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101452","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}
Pub Date : 2026-02-02DOI: 10.1097/hep.0000000000001703
Hayato Nakagawa
{"title":"Thawing “cold” tumors: The NRF2–COX2–PGE2 axis as a pathway to precision immunotherapy in HCC","authors":"Hayato Nakagawa","doi":"10.1097/hep.0000000000001703","DOIUrl":"https://doi.org/10.1097/hep.0000000000001703","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"94 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101435","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}
Pub Date : 2026-02-02DOI: 10.1097/hep.0000000000001701
Jonggi Choi, Junqing Xu, Vy H. Nguyen, Eric Przybyszewski, Daniel S. Pratt, Jiunn Song, Allison Carroll, Megan Michta, Erik Almazan, Tracey G. Simon, Raymond T. Chung
Background and Aims: Statins have been investigated for their potential to reduce liver-related complications in chronic liver diseases, but evidence in primary biliary cholangitis (PBC) remains limited. This study aimed to assess the association between statin use and the risk of hepatic decompensation using a target trial emulation (TTE) design. Approach and Results: We performed a sequential TTE using two electronic health record databases: Mass General Brigham (MGB, Boston, USA) and Asan Medical Center (AMC, Seoul, Korea). Adults diagnosed with PBC between 2001 and 2024 were eligible. Statin use was defined as a cumulative duration of ≥90 days. In each monthly trial, statin initiators were matched 1:2 to non-users using propensity score matching. The primary outcome was hepatic decompensation; the secondary outcome was a composite major adverse liver outcome (MALO), including decompensation, hepatocellular carcinoma, and liver transplantation. Among 2,889 eligible patients, 443 statin users were matched to 886 non-users. Over a median follow-up of 3.8 years, hepatic decompensation occurred in 24 statin users (5.4%) and in 67 non-users (7.6%) (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.38–0.97). Statin use was also associated with a reduced risk of MALO (HR, 0.58; 95% CI: 0.38–0.89). Sensitivity analyses stratified by data source (MGB, HR 0.65; AMC, HR 0.60) and cirrhosis status (HR 0.70 for cirrhosis; HR 0.57 for without) showed similar directional trends. Conclusions: Statin use was consistently associated with a lower risk of hepatic decompensation and major liver events in patients with PBC, supporting a potential protective effect.
{"title":"Association between statin use and hepatic decompensation in patients with primary biliary cholangitis: A target trial emulation study","authors":"Jonggi Choi, Junqing Xu, Vy H. Nguyen, Eric Przybyszewski, Daniel S. Pratt, Jiunn Song, Allison Carroll, Megan Michta, Erik Almazan, Tracey G. Simon, Raymond T. Chung","doi":"10.1097/hep.0000000000001701","DOIUrl":"https://doi.org/10.1097/hep.0000000000001701","url":null,"abstract":"Background and Aims: Statins have been investigated for their potential to reduce liver-related complications in chronic liver diseases, but evidence in primary biliary cholangitis (PBC) remains limited. This study aimed to assess the association between statin use and the risk of hepatic decompensation using a target trial emulation (TTE) design. Approach and Results: We performed a sequential TTE using two electronic health record databases: Mass General Brigham (MGB, Boston, USA) and Asan Medical Center (AMC, Seoul, Korea). Adults diagnosed with PBC between 2001 and 2024 were eligible. Statin use was defined as a cumulative duration of ≥90 days. In each monthly trial, statin initiators were matched 1:2 to non-users using propensity score matching. The primary outcome was hepatic decompensation; the secondary outcome was a composite major adverse liver outcome (MALO), including decompensation, hepatocellular carcinoma, and liver transplantation. Among 2,889 eligible patients, 443 statin users were matched to 886 non-users. Over a median follow-up of 3.8 years, hepatic decompensation occurred in 24 statin users (5.4%) and in 67 non-users (7.6%) (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.38–0.97). Statin use was also associated with a reduced risk of MALO (HR, 0.58; 95% CI: 0.38–0.89). Sensitivity analyses stratified by data source (MGB, HR 0.65; AMC, HR 0.60) and cirrhosis status (HR 0.70 for cirrhosis; HR 0.57 for without) showed similar directional trends. Conclusions: Statin use was consistently associated with a lower risk of hepatic decompensation and major liver events in patients with PBC, supporting a potential protective effect.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"79 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101437","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}
Pub Date : 2026-02-02DOI: 10.1097/hep.0000000000001704
David S. Umbaugh, Liuyang Wang, Kuo Du, Rajesh Kumar Dutta, Seh Hoon Oh, Georgia Sofia Karachaliou, Manal F. Abdelmalek, Ayako Suzuki, Anna Mae Diehl
Background and Aims: Older age increases susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined. Approach and Results: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use strongly associated with suppression of senescence-related pathways. Statin use also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort. Conclusions: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.
{"title":"Age and sex influence transcriptomic responses to statin therapy that control liver aging during systemic metabolic dysfunction","authors":"David S. Umbaugh, Liuyang Wang, Kuo Du, Rajesh Kumar Dutta, Seh Hoon Oh, Georgia Sofia Karachaliou, Manal F. Abdelmalek, Ayako Suzuki, Anna Mae Diehl","doi":"10.1097/hep.0000000000001704","DOIUrl":"https://doi.org/10.1097/hep.0000000000001704","url":null,"abstract":"Background and Aims: Older age increases susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined. Approach and Results: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use strongly associated with suppression of senescence-related pathways. Statin use also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort. Conclusions: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"232 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101434","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}
Pub Date : 2026-02-01Epub Date: 2025-03-14DOI: 10.1097/HEP.0000000000001307
Ting Zhang, Chih-Jen Huang, Hai-Tao Chen, Yu-Han Huang, Mei-Hung Pan, Mei-Hsuan Lee, Mathias Viard, Allan Hildesheim, Ruth M Pfeiffer, Mary Carrington, Chien-Jen Chen, Bin Zhu, Tobias L Lenz, Deke Jiang, Hwai-I Yang, Zhiwei Liu
Background and aims: The human leukocyte antigen (HLA) locus is implicated in HCC among chronic HBV carriers. We investigated associations of HLA variants, amino acid polymorphisms, zygosity, and evolutionary divergence with HBV-related HCC in Han Chinese and explored biological mechanisms.
Approach and results: We examined the associations of HLA variants (imputed 4-digit classical alleles and amino acid polymorphisms), zygosity, and evolutionary divergence with HBV-related HCC in a discovery set (706 HBV-related HCC cases, 6197 chronic HBV carriers in Taiwan). Significant signals were validated in an independent set (636 cases, 560 controls in Qidong, Mainland China). We used logistic regression adjusted for sex, age, and top 10 genetic principal components, with a Bonferroni correction for multiple testing ( p <1.6×10 -4 ). We evaluated predicted peptide-binding affinities and control of viral load, viral population diversity, and inflammatory markers for significant signals. HLA-DQB1*03:01 was most significantly associated with HBV-related HCC in discovery and validation sets (OR meta-analysis =1.33, pmeta-analysis =2.6×10 -8 ). Three amino acids within the DQβ1 peptide-binding region, HLA-DQβ1Ala13, HLA-DQβ1Tyr26, and HLA-DQβ1Glu45, were positively associated with HCC. HLA-DQB1*03:01 was associated with lower binding affinity of HBV nucleocapsid antigen and higher HBV DNA load and serum soluble programmed cell death 1 (sPD-1) ( p <0.05). HLA-DQB1 heterozygosity was inversely associated with HCC independent of HLA-DQB1*03:01 ( pmeta-analysis =3.3×10 -3 ).
Conclusions: HLA-DQB1*03:01 and its 3 key amino acids are associated with an increased HBV-related HCC risk. This association may be explained by the low binding affinity to HBV antigen, resulting in poor control of viral load and increased inflammation, as evidenced by sPD-1 levels.
{"title":"HLA-DQB1*03:01 and risk of HBV-related HCC.","authors":"Ting Zhang, Chih-Jen Huang, Hai-Tao Chen, Yu-Han Huang, Mei-Hung Pan, Mei-Hsuan Lee, Mathias Viard, Allan Hildesheim, Ruth M Pfeiffer, Mary Carrington, Chien-Jen Chen, Bin Zhu, Tobias L Lenz, Deke Jiang, Hwai-I Yang, Zhiwei Liu","doi":"10.1097/HEP.0000000000001307","DOIUrl":"10.1097/HEP.0000000000001307","url":null,"abstract":"<p><strong>Background and aims: </strong>The human leukocyte antigen (HLA) locus is implicated in HCC among chronic HBV carriers. We investigated associations of HLA variants, amino acid polymorphisms, zygosity, and evolutionary divergence with HBV-related HCC in Han Chinese and explored biological mechanisms.</p><p><strong>Approach and results: </strong>We examined the associations of HLA variants (imputed 4-digit classical alleles and amino acid polymorphisms), zygosity, and evolutionary divergence with HBV-related HCC in a discovery set (706 HBV-related HCC cases, 6197 chronic HBV carriers in Taiwan). Significant signals were validated in an independent set (636 cases, 560 controls in Qidong, Mainland China). We used logistic regression adjusted for sex, age, and top 10 genetic principal components, with a Bonferroni correction for multiple testing ( p <1.6×10 -4 ). We evaluated predicted peptide-binding affinities and control of viral load, viral population diversity, and inflammatory markers for significant signals. HLA-DQB1*03:01 was most significantly associated with HBV-related HCC in discovery and validation sets (OR meta-analysis =1.33, pmeta-analysis =2.6×10 -8 ). Three amino acids within the DQβ1 peptide-binding region, HLA-DQβ1Ala13, HLA-DQβ1Tyr26, and HLA-DQβ1Glu45, were positively associated with HCC. HLA-DQB1*03:01 was associated with lower binding affinity of HBV nucleocapsid antigen and higher HBV DNA load and serum soluble programmed cell death 1 (sPD-1) ( p <0.05). HLA-DQB1 heterozygosity was inversely associated with HCC independent of HLA-DQB1*03:01 ( pmeta-analysis =3.3×10 -3 ).</p><p><strong>Conclusions: </strong>HLA-DQB1*03:01 and its 3 key amino acids are associated with an increased HBV-related HCC risk. This association may be explained by the low binding affinity to HBV antigen, resulting in poor control of viral load and increased inflammation, as evidenced by sPD-1 levels.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"374-386"},"PeriodicalIF":15.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623027","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}
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