Journal of Hepatology最新文献

{"title":"Overcoming drug resistance by harnessing mitochondrial divisome for treating cholangiocarcinoma","authors":"Mengwei Niu, Wen-Xing Ding","doi":"10.1016/j.jhep.2025.04.038","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.038","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Competing interests</h2>The authors declare no conflicts of interest that pertain to this work.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section><section><section><h2>Authors’ contributions</h2>M.W &amp; WXD conceived and wrote the manuscript.</section></section><section><section><h2>Data Availability Statement:</h2>There are no data associated with this study.</section></section><section><section><h2>Financial support</h2>This study was supported in part by the National Institute of Health (NIH) funds R37 AA020518, R21 AA030617 and R01AA031230 (WXD).</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"76 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931300","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":"Carvedilol is superior to propranolol in preventing first and further decompensation, and mortality in patients with cirrhosis","authors":"Maria Christaki, Dimitrios Biros, Ilias Tsiakas, Haralampos Milionis, Georgios N. Kalambokis","doi":"10.1016/j.jhep.2025.04.032","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.032","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors' contributions</h2>MC, DB, IT and HM participated in the design of the study and contributed to the concept of the letter. GK interpreted the data and drafted the manuscript. All authors critically revised the manuscript and approved its final draft.</section></section><section><section><h2>Data availability statement</h2>Data are available on reasonable request.All authors confirm that we did not and will not submit the data included in the letter as original publication elsewhere.</section></section><section><section><h2>Financial support</h2>The authors received no financial support to produce this manuscript.</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors declare no conflicts of interest that pertain to this work.<ul><li><span></span><span>Please refer to the accompanying ICMJE disclosure forms for further details.</span></li></ul></section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"96 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920308","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":"Decoding the Resistin-CAP1 Pathway in Intermediate Monocytes Mediating Liver Allograft Rejection","authors":"Peijun Yang, Xudan Wang, Weikang Wu, Juzheng Yuan, Xinrui Wang, Rui Ding, Weiwei Cao, Cong Li, Yinjie Wang, Zihan Xi, Kefeng Dou, Xiao Li, Kaishan Tao","doi":"10.1016/j.jhep.2025.04.037","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.037","url":null,"abstract":"<h3>Background &amp; Aims</h3>Lymphocytes are widely recognized as the primary mediators of cellular rejection post-liver transplantation. However, conventional immunosuppressive regimens that target lymphocytes, such as calcineurin phosphatase inhibitors, corticosteroids, or lymphocyte-depleting antibodies, can only partially mitigate rejection while inducing severe adverse effects. This necessitates the search for novel immunotherapeutic targets.<h3>Methods</h3>We harnessed the power of single-cell RNA sequencing and spatial transcriptome in 24 rat transplanted liver and peripheral blood single nucleated cells (PBMCs) samples to derive gene expression signatures recapitulating 13 cell phenotypes. We used flow cytometry, multifactor assays and multiple recombinant assays to validate <em>in vitro</em> and <em>in vivo</em> the role of the target protein Resistin on human T-cell function, as well as the Resistin-CAP1 interaction. Gold nanoparticles were used to package <em>Retn</em> siRNA sequences to validate the role of <em>Retn</em> knockdown on acute rejection after liver transplantation.<h3>Results</h3>By distinguishing between donor and recipient cells, we delineate the dynamic landscape of immune cells during allograft rejection and their spatial distributions across donors and recipients. Our findings underscore the pivotal role of recipient derived intermediate monocytes in cellular rejection. Using CellChat ligand-receptor analysis, we identify the Resistin-CAP1 pathway as a key mechanism by which intermediate monocytes participate in T cell-mediated rejection reactions. We confirm that Resistin knockdown significantly alleviates acute rejection after rat liver transplantation, markedly extending the survival of recipients using innovative nanogold technology.<h3>Conclusion</h3>These findings offer insights into the dynamic changes in the alloimmune microenvironment, pinpointing intermediate monocytes as potential diagnostic and immunotherapeutic targets during allograft rejection. This study holds significant importance in advancing non-invasive diagnostic technologies and immunotherapeutic strategies for allogeneic rejection.<h3>Impact and implications</h3>This study pioneers the application of spatial transcriptomics in liver transplantation, providing a comprehensive analysis of immune cell spatial distribution, complemented by Souporcell-based chimerism assessment. We demonstrate that intermediate monocytes play a pivotal role in T cell-mediated acute rejection via the Resistin-CAP1 signaling axis. Targeting this pathway using nanogold-siRNA technology effectively mitigates rejection and enhances graft survival. These findings contribute novel insights into the mechanisms of transplant rejection and present promising avenues for the development of targeted therapeutic and diagnostic strategies in liver transplantation.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"25 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920307","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":"High inherited risk predicts age-associated increases in fibrosis in patients with MASLD","authors":"Luis Antonio Díaz, William Alazawi, Saaket Agrawal, Juan Pablo Arab, Marco Arrese, Francisco Idalsoaga, Fernando Javier Barreyro, Adrian Gadano, Sebastián Marciano, Jorge Martínez Morales, Cristiane Villela-Nogueira, Nathalie Leite, Claudia Alves Couto, Rafael Theodoro, Mísia Joyner de Sousa Dias Monteiro, Claudia P. Oliveira, Mario G. Pessoa, Mario Reis Alvares-da-Silva, Egbert Madamba, Ricki Bettencourt, Veeral Ajmera","doi":"10.1016/j.jhep.2025.04.035","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.035","url":null,"abstract":"<h3>Background &amp; Aims</h3>Limited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in MASLD.<h3>Methods</h3>This cross-sectional study included prospectively recruited adults with MASLD aged 18–70 who underwent magnetic resonance elastography (MRE) and genotyping for <em>PNPLA3, TM6SF2, MBOAT7, GCKR,</em> and <em>HSD17B13</em>. A genetic risk score (GRS) was calculated as the sum of established risk alleles in <em>PNPLA3</em> minus protective variants in <em>HSD17B13</em> (0=low risk, 1=high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.<h3>Results</h3>Among 570 participants, the median age was 57 [49–64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1–3.0] kPa, and 51% had high GRS. High GRS was independently associated with increased LSM (β=0.28 kPa, 95%CI:0.12–0.44, p=0.001) per 10-year age increase, while the low GRS group showed no significant difference. Similar findings were observed using PRS-HFC and PRS-5. <em>PNPLA3</em> genotype alone also predicted higher LSM (C/G: β=0.32 kPa, 95%CI:0.02–0.61, p=0.034; G/G: β=0.87 kPa, 95%CI:0.52–1.22, p&lt;0.0001) and G/G genotype was associated with significantly higher LSM by age 44, which was consistent in the validation population.<h3>Conclusion</h3>GRS, PRS-HFC, PRS-5, and <em>PNPLA3</em> genotypes alone are associated with greater fibrosis per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring.<h3>IMPACT AND IMPLICATIONS</h3>This study provides granular evidence that genetic predisposition, particularly the <em>PNPLA3</em> G/G genotype, significantly influences the trajectory of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), with a more pronounced impact emerging after the fourth decade of life. These findings highlight the importance of incorporating genetic risk assessment into MASLD management, as it allows for the early identification of high-risk individuals who may benefit from more frequent monitoring and targeted interventions. Given the rising global burden of MASLD, clinicians, researchers, and policymakers should consider integrating genetic stratification into existing risk assessment frameworks to refine screening and surveillance strategies. By optimizing patient selection for non-invasive fibrosis assessment and potential therapeutic interventions, this approach could enhance precision medicine efforts and may improve long-term outcomes.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"21 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910656","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":"Does the UK DCD Risk Score have statistical flaws?","authors":"Simon Schwab, Vanessa Banz, Ulrike Held, Linard Hoessly, Giulia Magini","doi":"10.1016/j.jhep.2025.04.030","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.030","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors' contributions</h2>SS drafted the manuscript and performed the analysis. All authors revised, reviewed, and approved the final manuscript.</section></section><section><section><h2>Financial support</h2>The authors received no financial support to produce this letter.</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors declare no conflicts of interest associated with this letter.Please refer to the accompanying ICMJE disclosure forms for further details.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"46 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905718","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":"New platinum derivatives selectively cause double-strand DNA breaks and death in naïve and cisplatin-resistant cholangiocarcinomas","authors":"Irene Olaizola, Mikel Odriozola-Gimeno, Paula Olaizola, Francisco J. Caballero-Camino, Noelia Pastor-Toyos, Mireia Tena-Garitaonandia, Ainhoa Lapitz, Beatriz Val, Amanda R. Guimaraes, Maitane Asensio, Maider Huici-Izagirre, Colin Rae, David de Sancho, Xabier Lopez, Pedro M. Rodrigues, Elisa Herraez, Oscar Briz, Laura Izquierdo-Sanchez, Aitziber Eleta-Lopez, Alexander M. Bittner, Jesus M. Banales","doi":"10.1016/j.jhep.2025.04.034","DOIUrl":"https://doi.org/10.1016/j.jhep.2025.04.034","url":null,"abstract":"<h3>Background &amp; Aims</h3>Patients with cholangiocarcinoma (CCA) have poor prognosis. Current cisplatin-based first-line chemotherapy offers limited survival benefits. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. Here, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents (Aurkines) with unique polyelectrophilic properties. These agents cause a high frequency of double-strand DNA breaks, bypassing DNA repair, and promoting cancer cell death.<h3>Methods</h3>Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumor effects in both naïve and cisplatin-resistant CCA cells, cancer-associated fibroblasts (CAFs), healthy cholangiocytes, and <em>in vivo</em> models.<h3>Results</h3>Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity than cisplatin in CCA cells. Phosphoproteomic and molecular analysis revealed that cisplatin activates DNA repair pathways, while Aurkines primarily induce apoptosis. Importantly, Aurkines also triggered apoptosis in cisplatin-resistant CCA cells and CAFs without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other cisplatin-resistant cancers, such as breast and ovarian cancer. This tumor selectivity results from reduced uptake, increased efflux, and compact chromatin structure in normal cells, limiting Aurkine-DNA interactions. <em>In vivo</em>, Aurkines inhibited the growth of subcutaneous naïve and cisplatin-resistant CCA tumors, as well as orthotopic tumors in immunocompetent mice promoting antitumor immune cell recruitment, without any adverse events. Transport studies revealed that Aurkines were selectively taken up by OCT1, OCT3, CTR1, and OATP1A2, whereas only CTR1 transported cisplatin.<h3>Conclusions</h3>Aurkines represent promising therapeutic drugs for both naïve and cisplatin-resistant cancers due to their unique polyelectrophilic properties and selective targeting of malignant cells.<h3>Impact and implications</h3>This study introduces a novel therapeutic strategy designed to induce frequent double-strand DNA breaks selectively in both naïve and cisplatin-resistant cancer cells, without evident toxic side effects at therapeutic doses. This approach may settle the basis for new strategies to overcome the critical challenge of drug resistance in cancer treatment, and has the potential to be a breakthrough not only for the treatment of biliary tumors but also for other cancers.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"36 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905722","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":"OS-022 Patient-level analysis of intrahepatic z-alpha-1 antitrypsin burden in patients with alpha-1 antitrypsin deficiency-associated liver disease following fazirsiran treatment","authors":"Virginia C. Clark,&nbsp;Jen-Chieh Chuang,&nbsp;Feng Hong,&nbsp;Vandana Gupta,&nbsp;Ran Ye,&nbsp;Natasha Darras,&nbsp;Alexander J. Prokopienko,&nbsp;Susana Gonzalez,&nbsp;Paresh Thakker,&nbsp;Nirav K. Desai,&nbsp;Thomas Schluep,&nbsp;James Hamilton,&nbsp;Pavel Strnad,&nbsp;Rohit Loomba","doi":"10.1016/S0168-8278(25)00337-X","DOIUrl":"10.1016/S0168-8278(25)00337-X","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"82 ","pages":"Pages S24-S25"},"PeriodicalIF":26.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911638","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":"OS-002-YI Identifying training needs to improve detection and management of metabolic dysfunction-associated steatotic liver disease in primary care settings: a qualitative interview study with healthcare professionals","authors":"Hollie Smith,&nbsp;Rebecca Livingston,&nbsp;Helen Jarvis,&nbsp;Yusuf Soni,&nbsp;Stuart McPherson,&nbsp;Leah Avery,&nbsp;Kate Hallsworth","doi":"10.1016/S0168-8278(25)00317-4","DOIUrl":"10.1016/S0168-8278(25)00317-4","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"82 ","pages":"Pages S13-S14"},"PeriodicalIF":26.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911714","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":"GS-012 Efruxifermin improves fibrosis in participants with compensated cirrhosis due to MASH: results of a 96-week, randomized, doubleblind, placebo-controlled, phase 2b trial (SYMMETRY)","authors":"Mazen Noureddin,&nbsp;Mary E. Rinella,&nbsp;Naga Chalasani,&nbsp;Guy Neff,&nbsp;Kathryn Lucas,&nbsp;Manuel Rodriguez,&nbsp;Madhavi Rudraraju,&nbsp;Rashmee Patil,&nbsp;Cynthia Behling,&nbsp;Mark Burch,&nbsp;Doreen Chan,&nbsp;Erik Tillman,&nbsp;Arian Zari,&nbsp;Brittany de Temple,&nbsp;Reshma Shringarpure,&nbsp;Meena Jain,&nbsp;Tim Rolph,&nbsp;Andrew Cheng,&nbsp;Kitty Yale","doi":"10.1016/S0168-8278(25)00309-5","DOIUrl":"10.1016/S0168-8278(25)00309-5","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"82 ","pages":"Pages S8-S9"},"PeriodicalIF":26.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911957","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":"OS-030-YI Discrepancies between self-reported alcohol intake and phosphatidylethanol in 2,925 individuals at risk of steatotic liver disease","authors":"Katrine Bech,&nbsp;Nikolaj Torp,&nbsp;Helle Schnefeld,&nbsp;Georg Semmler,&nbsp;Javier Vega,&nbsp;Katrine Prier Lindvig,&nbsp;Katrine Thorhauge,&nbsp;Stine Johansen,&nbsp;Ellen Lyngbeck Jensen,&nbsp;Ellen Elise Petersen,&nbsp;Johanne Kragh Hansen,&nbsp;Camilla Dalby Hansen,&nbsp;Ida Falk Villesen,&nbsp;Peter Andersen,&nbsp;Aleksander Krag,&nbsp;Mads Israelsen,&nbsp;Maja Thiele","doi":"10.1016/S0168-8278(25)00345-9","DOIUrl":"10.1016/S0168-8278(25)00345-9","url":null,"abstract":"","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"82 ","pages":"Page S28"},"PeriodicalIF":26.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911530","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}