Journal of Hepatology最新文献

{"title":"Prevalence, severity and determinants of steatotic liver disease among individuals with metabolic and alcohol risk from the community","authors":"Camilla Dalby Hansen, Johanne Kragh Hansen, Mads Israelsen, Peter Andersen, Laura Maarit Pikkupeura, Katrine Prier Lindvig, Sara Elizabeth Stinson, Helle Lindholm Schnefeld, Julie Tellerup, Maria Fogt, Nikolaj Torp, Maria Kjærgaard, Katrine Tholstrup Bech, Katrine Holtz Thorhauge, Stine Johansen, Ida Spedtsberg, Emil Deluran, Ida Falk Villesen, Sönke Detlefsen, Torben Hansen, Maja Thiele","doi":"10.1016/j.jhep.2025.06.020","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.020","url":null,"abstract":"<h3>Background &amp; Aims</h3>Individuals with steatotic liver disease (SLD) are affected by metabolic dysfunction and/or high alcohol consumption; however, the prevalence of SLD in at-risk individuals remains underexplored. In at-risk individuals, we aimed to investigate the prevalence and severity of SLD and subclasses: metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic and alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD)<h3>Methods</h3>Between Oct 2017 and Nov 2022, citizens aged 30-75 years were recruited 1:1 into: a) Metabolic cohort with BMI &gt;30 kg/m² and/or type 2 diabetes without prolonged increased alcohol consumption, b) Alcohol cohort with ongoing/prior increased alcohol consumption. We assessed liver steatosis by controlled attenuation parameter (CAP), liver fibrosis by liver stiffness measurements (LSM) and performed liver biopsies in participants with LSM ≥8 kPa.<h3>Results</h3>We included 3,123 participants; 1,599 in the metabolic cohort and 1,524 in the alcohol cohort. In total, 2,197 (70%) were diagnosed with SLD:1,603 (51%) with MASLD, 398 (13%) with MetALD, and 196 (6.3%) with ALD. Of 307 (9.8%) with LSM ≥8 kPa, 169 underwent liver biopsy (55%). In the metabolic cohort, 1,237 (77%) had SLD, 147 (9.2%) had LSM ≥8 kPa, and 24 (1.5%) had biopsy-confirmed advanced liver fibrosis. In the alcohol cohort, 960 (63%) had SLD, 160 (10.5%) had LSM ≥8 kPa, and 46 (3.1%) had biopsy-confirmed advanced liver fibrosis. Across subclasses, ALD demonstrated highest liver disease severity (LSM ≥8 kPa: 25%; biopsy-confirmed advanced fibrosis: 8%), and severity was comparable between MASLD and MetALD (LSM ≥8 kPa: 12%, biopsy-confirmed advanced fibrosis: 3%).<h3>Conclusions</h3>Among individuals with cardiometabolic and/or alcohol risk factors, 70% had SLD, 10% had elevated liver stiffness, and 2% had biopsy-confirmed advanced liver fibrosis.Clinicaltrials.gov: NCT03308916<h3>Impact and implications</h3>Steatotic liver disease (SLD) remains underdiagnosed in the general population. This study provides new population-based data on its prevalence and severity among individuals with metabolic and/or alcohol-related risk. These findings are relevant to clinicians, researchers, and public health planners, as prevalence data are essential to inform evolving screening strategies. Methodological limitations, including the cross-sectional design and limited generalizability, should be considered when interpreting the results.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"6 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565643","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":"Mechanisms and Management of Graft In- and Out-flow in Liver Transplantation: A Narrative Review of the Literature and Guide for Interventional Management","authors":"Chase J. Wehrle, Masato Fujiki, Sangeeta Satish, Giuseppe Iuppa, Luis Campos, Federico Aucejo, David CH. Kwon, Andrea Schlegel, Antonio D. Pinna, Koji Hashimoto, Charles Miller, Cristiano Quintini, Teresa Diago Uso","doi":"10.1016/j.jhep.2025.06.024","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.024","url":null,"abstract":"<h3>Background and Aims</h3>Management of the dual vascular supply of liver grafts in liver transplantation (LT) is increasingly recognized as crucial to achieving adequate graft function. We aim to review how the relationship between graft in-flow and out-flow affects graft function, and how surgeons can manage graft function within the context of liver hemodynamic autoregulation. This includes mechanisms of such autoregulation including the hepatic artery buffer response (HABR), and the impact of porto-systemic circulatory changes on graft inflow.<h3>Methods &amp; Results (Review)</h3>This study represents a narrative review of the literature along with the editorial input/practices of the authors. A complex mechanistic understanding can guide surgeons in the management of common and even un-common vascular conditions after transplantation. Portal hyperperfusion is the most common, usually resulting from decreased intrahepatic adenosine and arterial vasoconstriction via the HABR. Such a concern is now recognized as the treatment of Small-for-Size Syndrome, and thus management of vascular in- and out-flow is also critical to the use of small liver grafts to preserve donor safety. Portal inflow modulation (PIM) using splanchnic vasodilators, splenic embolization, or splenectomy are all recognized treatments for hyperperfusion. However, the management of portal hypo-perfusion is less well described, with only isolated case reports describing the augmentation of portal venous in-flow. Finally, the impact of graft out-flow is reviewed, with a focus on how out-flow can improve graft utility in living donor liver transplantation.<h3>Conclusions</h3>Overall, an understanding of complex hepatic vascular regulation is essential to optimizing liver graft function in transplantation. This review may help surgeons as they continue to strive for improved access to transplantation across the world.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"457 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565644","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":"Reframing The Spectrum of Steatotic Liver Disease as a Dynamic Concept","authors":"Zobair M. Younossi, Shira Zelber-Sagi, Aleksander Krag","doi":"10.1016/j.jhep.2025.06.026","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.026","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Data Availability</h2>Not applicable</section></section><section><section><h2>Author Contributions:</h2>Zobair M. Younossi- study design, critical writing and editing of the manuscriptShira Zelber-Sagi- study design, critical writing and editing of the manuscriptAleksander Krag -study design, critical writing and editing of the manuscript</section></section><section><section><h2>Funding</h2>This letter was partially funded by the Global NASH and the Global Liver Councils, the Beatty Center for Liver and Obesity Research and the Center for Outcomes Research in Liver Disease</section></section><section><section><h2>Declaration of Competing Interest</h2>Zobair M. Younossi is a consultant or has received research funding from Intercept, Cymabay, Boehringer Ingelheim, Ipsen, Gilead Sciences, Inventiva, BMS, GSK, NovoNordisk, Siemens, Madridgal, Merck, Akero and Abbott. All other authors have no conflicts of interest to declare relevant for this manuscript</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"27 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565797","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":"Somatic loss-of-function mutations in CIDEB reduce hepatic steatosis by increasing lipolysis and fatty acid oxidation","authors":"Qiyu Zeng, Satish Patel, Xun Wang, Meng-Hsiung Hsieh, Zhijie Li, Xiongzhao Ren, Jingjing Wang, Dohun Kim, Shili Li, Xinping Gu, Greg Mannino, Gianna Maggiore, Xiangyi Fang, Lin Li, Min Zhu, Mengmeng Wang, Boyuan Li, Amaey Bellary, Koini Lim, Zhetuo Qi, Hao Zhu","doi":"10.1016/j.jhep.2025.06.021","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.021","url":null,"abstract":"<h3>Background &amp; Aims</h3>Somatic and germline <em>CIDEB</em> mutations are associated with protection from chronic liver diseases. The mechanistic basis and whether <em>CIDEB</em> suppression would be an effective therapy against fatty liver disease remain unclear.<h3>Methods</h3>21 <em>CIDEB</em> somatic mutations were introduced into cells to assess functionality. In vivo screening was used to trace <em>Cideb</em> mutant clones in mice fed normal chow, western (WD), and choline-deficient, L-amino acid-defined, high-fat (CDA-HFD) diets. Constitutive and conditional <em>Cideb</em> knockout mice were generated to study <em>Cideb</em> in liver disease. Isotope tracing was used to evaluate fatty acid oxidation and de novo lipogenesis. Transcriptomics, lipidomics, and metabolic analyses were utilized to explore molecular mechanisms. Double knockout models (<em>Cideb/Atgl</em> and <em>Cideb/Pparα</em>) tested mechanisms underlying <em>Cideb</em> loss.<h3>Results</h3>Most <em>CIDEB</em> mutations showed that they impair function, and lineage-tracing showed that loss-of-function clones were positively selected with CDA-HFD, but not all fatty liver inducing diets. <em>Cideb</em> KO mice were protected from WD, CDA-HFD, and alcohol diets, but had the greatest impact on CDA-HFD induced liver disease. Hepatocyte-specific <em>Cideb</em> deletion could ameliorate disease after metabolic dysfunction-associated steatotic liver disease (MASLD) establishment, modeling the impact of therapeutic siRNAs. <em>Cideb</em> loss protected livers via increased β-oxidation, specifically through ATGL and PPARα activation.<h3>Conclusions</h3><em>Cideb</em> deletion is more protective in some types of fatty liver disease. β-oxidation is an important component of the <em>Cideb</em> protective mechanism. <em>CIDEB</em> inhibition represents a promising approach, and somatic mutations in <em>CIDEB</em> might predict the patient populations that might benefit the most.<h3>Impact and Implications</h3>It is not clear why somatic and germline <em>CIDEB</em> mutations are protective in MASLD. <em>Cideb</em> mutations are predominantly loss of function, and <em>Cideb</em>-deficient clones selectively expand in specific dietary contexts such as CDA-HFD-induced MASLD. Consistently, liver-wide deletion of <em>Cideb</em> ameliorates MASLD most profoundly after CDA-HFD feeding. Mechanistically, <em>Cideb</em> deficiency enhances hepatic fatty acid β-oxidation via ATGL and PPARα activation. These findings suggest that <em>CIDEB</em> inhibition might be most effective in patients with the subtypes of MASLD that promote the expansion of <em>CIDEB</em> mutant clones.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"20 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565779","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":"Spatiotemporal liver dynamics shape hepatocellular heterogeneity and impact in vivo gene engineering","authors":"Michela Milani, Francesco Starinieri, Stefano Beretta, Marco Monti, Cesare Canepari, Francesca Marabotti, Samuel Zambrano, Davide Mazza, Anna Fabiano, Chiara Simoni, Eugenia Cammarota, Monica Volpin, Giulia Bortolussi, Fabio Russo, Mauro Biffi, Marco Genua, Sara Degl’Innocenti, Francesca Sanvito, Renato Ostuni, Andrés F. Muro, Alessio Cantore","doi":"10.1016/j.jhep.2025.06.018","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.018","url":null,"abstract":"&lt;h3&gt;Background and Aims&lt;/h3&gt;Hepatocytes are the primary cells of the liver, essential for metabolism and important targets for &lt;em&gt;in vivo&lt;/em&gt; gene therapy, which has the potential to treat monogenic diseases caused by defects in their functions. Integrating the transgene into the target cell’s genome is crucial for long-term expression following a single dose administered early in life, achievable through integrating vectors or genome editing. To ensure the persistence of the genetic modification throughout liver growth and turnover, it is also necessary to target the cells involved in these processes. Although previous research has focused on liver homeostasis and regeneration, the growth and maturation of hepatocytes remain not fully understood. Here, we explore the evolution of hepatocyte heterogeneity during liver growth and evaluate its implications for &lt;em&gt;in vivo&lt;/em&gt; gene engineering.&lt;h3&gt;Methods&lt;/h3&gt;We performed clonal tracing, single-cell and spatial transcriptomics on mouse livers of various ages. We evaluated the efficiency, stability, and lobule distribution of lentiviral gene transfer and targeted transgene integration.&lt;h3&gt;Results&lt;/h3&gt;We found that a subset of clonogenic hepatocytes (15-20%) in the newborn liver generates &gt;90% of the adult tissue and co-localizes with hematopoietic islands within a spatial niche. Preferential gene editing of these clonogenic hepatocytes resulted in an increased proportion of the gene-engineered liver area, supporting their role in liver growth. Age-dependent hepatocellular heterogeneity affected the efficiency of lentiviral gene delivery &lt;em&gt;in vivo&lt;/em&gt; and its distribution throughout the hepatic lobule. The gradual establishment of metabolic zonation after weaning and elevated proteasome activity in the peri-central area in adults influenced the observed age-related outcomes.&lt;h3&gt;Conclusion&lt;/h3&gt;These insights into spatiotemporal hepatocyte dynamics enhance our understanding of liver biology and have important implications for therapeutic strategies.&lt;h3&gt;Impact and implications&lt;/h3&gt;We provide new insights into the spatiotemporal dynamics of the mouse liver during postnatal growth, highlighting both proliferative and transcriptomic heterogeneity among hepatocytes and their impact on the efficiency and distribution of &lt;em&gt;in vivo&lt;/em&gt; lentiviral gene delivery and targeted gene editing. Understanding and manipulating the biological processes behind this heterogeneity can enhance gene transfer outcomes. We report that not all hepatocytes contribute equally to liver growth, indicating that effectively targeting clonogenic hepatocytes in the newborn liver is crucial for the long-term maintenance of therapeutic genetic modifications. Furthermore, this phenomenon can be leveraged to expand the pool of genetically corrected cells, as illustrated here by a targeted gene editing strategy. Finally, we reveal the existence of a tissue niche that supports the proliferation of both clonogenic hepatocytes and he","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"27 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547427","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":"Staging decompensated cirrhosis: Lumping, splitting, or just rearranging the deck chairs on the Titanic?","authors":"Alina M. Allen, Patrick S. Kamath","doi":"10.1016/j.jhep.2025.04.039","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.039","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Financial support</h2>The authors did not receive any financial support to produce this manuscript.</section></section><section><section><h2>Authors’ contributions</h2>Both authors contributed equally to this manuscript.</section></section><section><section><h2>Conflict of interest</h2>The authors of this study declare that they do not have any conflict of interest.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"1 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144521121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of liver biopsy in diagnosing patients with autoimmune hepatitis- it can be acceptable to skip!","authors":"Einar Stefan Björnsson, Gideon M. Hirschfield","doi":"10.1016/j.jhep.2025.06.017","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.017","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors' contributions</h2>Both authors contributed to the conception of the work together. ESB drafted the Letter and both critically reviewed and revised the manuscript draft and approved the final version for submission.</section></section><section><section><h2>Financial support</h2>The authors did not receive any financial support for the writing of the Letteer.</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors did not have any conflicts of interest related to the topic of this article.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"3 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The endothelium as the gatekeeper of insulin’s action on metabolic tissues: Implications for MASLD and MASH","authors":"Thomas Marjot","doi":"10.1016/j.jhep.2025.06.001","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.001","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"77 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515624","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":"Phase 1 randomized double-blind study of an RNA interference therapeutic targeting HSD17B13 for metabolic dysfunction–associated steatohepatitis","authors":"Arun J. Sanyal, Jorg Taubel, Prajakta Badri, Sarah Bond, Nune Makarova, Weizhi Zhao, Swati Duggal, Farshad Kajbaf, Benjamin A. Olenchock, John M. Gansner","doi":"10.1016/j.jhep.2025.05.031","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.05.031","url":null,"abstract":"Genome-wide association studies have identified loss-of-function variants in the hydroxysteroid 17-beta dehydrogenase 13 gene (<ce:italic>HSD17B13</ce:italic>) associated with reduced risk of chronic liver disease. In this Phase 1 study, we evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of rapirosiran, an investigational, <ce:italic>N</ce:italic>-acetylgalactosamine (GalNAc)-conjugated small interfering RNA targeting liver-expressed mRNA for <ce:italic>HSD17B13</ce:italic>.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"30 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144515622","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":"Antibodies elicited by hepatitis E vaccination in humans confer cross-genus protection against rat hepatitis E virus","authors":"Zihao Chen, Liqin Liu, Jianwen Situ, Guanghui Li, Shaoqi Guo, Qi Lai, Shusheng Wu, Yanan Jiang, Jingyan Fan, Zimin Tang, Yu Li, Guiping Wen, Siling Wang, Dong Ying, Yonghao Liang, Stanley Siu-Fung Ho, Xiaodan Ma, James Yiu-Hung Tsoi, Estie Hon-Kiu Shun, Nicholas Foo-Siong Chew, Zizheng Zheng","doi":"10.1016/j.jhep.2025.06.015","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.06.015","url":null,"abstract":"<h3>Background &amp; Aims</h3><em>Paslahepevirus balayani</em> (bHEV), also known as hepatitis E virus (HEV), encompasses eight genotypes, five of which infect humans. Rats are natural reservoirs of <em>Rocahepevirus ratti</em> genotype 1 (HEV-<em>r</em>-1; rat HEV; rHEV), which has recently been implicated in viral hepatitis. Despite the antigenic divergence between bHEV and rHEV, studies on shared protective antibodies remain rare.<h3>Methods</h3>Polyclonal and monoclonal antibody responses against bHEV and rHEV were analyzed using antibody enzyme-linked immunosorbent assays. The efficacy of six potent bHEV-elicited cross-reactive antibodies in preventing rHEV infection was evaluated via challenge assays in rats. Cryo-EM was performed to assess the structural basis for the differential protective efficacy of the six antibodies. The viral lysis ability of these antibodies was assessed by separately reacting purified HEV-<em>b</em>-1 and HEV-<em>r</em>-1 virions with each antibody.<h3>Results</h3>We determined that antibody responses to bHEV infection and vaccination possess limited cross-reactivity to rHEV and identified two cross-reactive antigenic sites within the E2s domain. Structural analysis and animal challenge studies pinpointed potent cross-reactive antibodies targeting antigenic site 1, indicating its prophylactic efficacy against rHEV. Conversely, antibodies recognizing antigenic site 2 were found to facilitate viral lysis of bHEV but not rHEV.<h3>Conclusions</h3>These findings underscore the importance of antigenic site 1 in the design of broad-spectrum vaccines and therapeutics to mitigate the impact of diverse HEV genotypes on human health.<h3>Impact and implications</h3>rHEV spillover to humans represents an unprecedented threat. Significant antigenic differences between rHEV and bHEV may exacerbate the impact of viral hepatitis. Our study reveals that cross-reactive human antibodies can offer protection against rHEV infection. Cross-protective antibodies targeting antigenic site 1 can be used to inform the development of practical strategies for preventing rHEV infection.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"235 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479361","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}