JHEP Reports最新文献

{"title":"Navigating liver toxicity in the age of novel oncological agents","authors":"Mar Riveiro-Barciela ,&nbsp;Eleonora De Martin","doi":"10.1016/j.jhepr.2025.101473","DOIUrl":"10.1016/j.jhepr.2025.101473","url":null,"abstract":"<div><div>The advent of novel oncological therapies, including immune checkpoint inhibitors, antibody-drug conjugates, and protein kinase inhibitors, has revolutionised cancer treatment by significantly improving patient survival across a range of malignancies. However, these advances have been accompanied by the emergence of new and often unpredictable adverse events, among which hepatotoxicity represents a growing clinical challenge. In this review, we provide a comprehensive synthesis of current knowledge on liver injury associated with these three key classes of oncological agents, with a particular focus on mechanisms of action and hepatotoxicity, clinical presentation, and management strategies. Given the expanding use of these agents, both as monotherapies or in combination regimens, this topic is of pressing relevance to hepatologists and oncologists alike. As combination therapies become increasingly common, the complexity of drug–liver interactions and their implications for patient safety demand greater interdisciplinary awareness and collaboration. This review advocates for a pragmatic approach to the management of drug-induced liver injury in patients with cancer, underscoring the critical need to balance hepatic preservation with the imperative of maintaining oncological efficacy in this uniquely vulnerable population. By addressing an emerging area of clinical importance, we aim to stimulate further research on oncological hepatotoxicity, a phenomenon that is poised to become increasingly prevalent in routine clinical practice.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"Article 101473"},"PeriodicalIF":7.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772330","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":"Comparative risk of osteoporosis and fractures in chronic hepatitis B patients: Tenofovir disoproxil fumarate vs. entecavir in a Korean nationwide cohort.","authors":"Yoon E Shin, Jae Young Kim, Hyuk Kim, Jeong Ju Yoo, Sang Gyune Kim, Young Seok Kim","doi":"10.1016/j.jhepr.2025.101489","DOIUrl":"10.1016/j.jhepr.2025.101489","url":null,"abstract":"<p><strong>Background & aims: </strong>The optimal antiviral agent for patients with chronic hepatitis B (CHB) at risk for osteoporosis remains debated. The aim of this study was to compare the incidence of osteoporosis and osteoporotic fractures between patients treated with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) using a nationwide cohort in South Korea.</p><p><strong>Method: </strong>We analyzed 40,404 patients with CHB treated with either TDF (n = 23,779) or ETV (n = 16,625). The risk of osteoporosis and osteoporotic fractures was evaluated using Cox proportional hazards models, incidence rate ratios (IRRs), and Kaplan-Meier survival analysis. To adjust for baseline differences, inverse probability of treatment weighting was applied.</p><p><strong>Result: </strong>Over a mean follow-up of 50.8 months, osteoporosis occurred in 1,712 TDF users and 1,094 ET V users. The incidence rate of osteoporosis was significantly higher in the TDF group (IRR 1.30, 95% CI 1.23-1.37; <i>p <</i>0.001). Multivariate Cox regression also confirmed increased osteoporosis risk with TDF (hazard ratio [HR] 1.328, 95% CI 1.258-1.401; <i>p <</i>0.001), while fracture incidence was not significantly different (HR 1.027, 95% CI 0.939-1.122, <i>p</i> = 0.569). In patients aged ≥60 years, the TDF group had a significantly higher risk of both osteoporosis (HR 1.347, 95% CI 1.224-1.484; <i>p <</i>0.001) and fractures (HR 1.213, 95% CI 1.051-1.403; <i>p</i> = 0.009), with divergence in Kaplan-Meier curves evident after 1 and 3 years of treatment, respectively.</p><p><strong>Conclusion: </strong>Long-term use of TDF is associated with a significantly increased risk of osteoporosis and fractures, especially in patients aged ≥60 years. These findings support the need for proactive bone health surveillance in patients with CHB receiving long-term TDF therapy.</p><p><strong>Impact and implications: </strong>Our study highlights the need for careful antiviral selection in patients with chronic hepatitis B aged ≥60 due to the increased risk of osteoporosis and fractures with long-term tenofovir disoproxil fumarate use. We recommend using entecavir or tenofovir alafenamide fumarate as the preferred therapies for patients at high risk of fractures. Early intervention is essential, as fracture incidence tends to rise after 2-3 years of tenofovir disoproxil fumarate therapy, making regular bone mineral density monitoring critical for these patients.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"101489"},"PeriodicalIF":7.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873259","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}

{"title":"\"The alcohol-harm paradox\": Understanding socioeconomic inequalities in liver disease.","authors":"Laura Weichselbaum, Judah Kupferman, Allison J Kwong, Christophe Moreno","doi":"10.1016/j.jhepr.2025.101480","DOIUrl":"10.1016/j.jhepr.2025.101480","url":null,"abstract":"<p><p>The alcohol-harm paradox (AHP) refers to the fact that people from lower socioeconomic groups experience higher rates of alcohol-related illness despite consuming the same or even lower amounts of alcohol than their more affluent counterparts. While differences in drinking patterns and associations with other risky behaviours partially explain the paradox, they do not fully account for the disparities in morbidity and mortality across socioeconomic groups. The existence of an alcohol-harm paradox in liver disease has been demonstrated in many countries worldwide. Recently, the COVID-19 pandemic further exacerbated these differences and led to an increase in alcohol intake and alcohol-related mortality among racial and ethnic minorities in the United States. Approaches to limit alcohol sales, through introduction of minimum unit pricing or taxation, have led to reductions in alcohol-related liver disease, particularly in socioeconomically deprived areas. Disparities in access to treatment of alcohol use disorder, liver disease and liver transplantation further contribute to the AHP. This review focuses on the AHP, its impact on liver disease and the multi-level strategy that will be required to curb this phenomenon.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"101480"},"PeriodicalIF":7.5,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873257","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}

{"title":"Myeloid TGF-β signaling shapes liver macrophage heterogeneity and metabolic liver disease pathogenesis","authors":"Ziyi Meng ,&nbsp;Xiaoxue Qiu ,&nbsp;Zhimin Chen ,&nbsp;Yu-tung Lee ,&nbsp;Linkang Zhou ,&nbsp;You Lu ,&nbsp;Tongyu Liu ,&nbsp;Siming Li ,&nbsp;Benjamin Levi ,&nbsp;Katherine A. Gallagher ,&nbsp;Jiandie D. Lin","doi":"10.1016/j.jhepr.2025.101488","DOIUrl":"10.1016/j.jhepr.2025.101488","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cellular heterogeneity of innate immune cells, such as macrophages, in the liver is a hallmark of metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis. However, the mechanisms shaping liver macrophage heterogeneity and function during disease progression remain poorly understood.</div></div><div><h3>Methods</h3><div>Control or myeloid-specific <em>Tgfbr1</em> knockout mice (n = 9-12 per group) were fed a 12-week choline-deficient, amino acid-defined high-fat diet (CDA-HFD) or a 20-week GAN diet (40% fat, 22% fructose, 2% cholesterol). Liver tissue was analyzed using histopathology, quantitative PCR, immunoblotting, flow cytometry, and RNA sequencing (RNA-seq). Bulk RNA-seq (n = 3 per group) and single-nucleus RNA-seq were performed to investigate transcriptional reprogramming. Macrophage population dynamics were evaluated by flow cytometry and immunofluorescence.</div></div><div><h3>Results</h3><div>We identified TGF-β signaling as a crucial regulator of disease-associated expansion of Trem2⁺ and Fcrl5⁺ macrophages in MASH livers. Myeloid-specific inactivation of <em>Tgfbr1</em> in mice exacerbated diet-induced MASH, with increased hepatocyte injury, inflammation, and liver fibrosis. Mechanistically, loss of TGF-β signaling in myeloid cells altered macrophage composition, marked by a reduction in Trem2⁺ and expansion of Fcrl5⁺ macrophages. Additionally, macrophages lacking <em>Tgfbr1</em> exhibited gene signatures associated with inflammasome activation, cytokine signaling, cellular senescence, and immunosuppression. These changes in macrophage composition and function promoted effector T cell exhaustion and the development of MASH-associated hepatocellular carcinoma in <em>Tgfbr1</em>-deficient mice.</div></div><div><h3>Conclusions</h3><div>These findings identify myeloid TGF-β signaling as a key driver of liver macrophage heterogeneity and polarization within the microenvironment during the progression of MASH and MASH-associated liver cancer.</div></div><div><h3>Impact and implications</h3><div>Our study reveals that myeloid TGF-β signaling plays a crucial role in shaping liver macrophage heterogeneity, which in turn influences the pathogenesis of metabolic liver disease. These findings are particularly important for researchers studying immune-metabolic interactions and for clinicians seeking new therapeutic strategies for liver disorders. By elucidating how TGF-β signaling regulates macrophage function, our work paves the way for targeted interventions that modulate immune responses to improve liver health. Future research should consider the potential translational applications of these findings while addressing limitations related to model systems and human variability.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 8","pages":"Article 101488"},"PeriodicalIF":9.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633293","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":"Stiffness-activated hepatic stellate cells boost HCC migration via TGM2/ITGB1-mediated matrix remodeling and mitochondrial transfer","authors":"Man Wang ,&nbsp;Yannan Xu ,&nbsp;Yongbin Meng ,&nbsp;Wei Xie ,&nbsp;Jun Chen ,&nbsp;Juan Du","doi":"10.1016/j.jhepr.2025.101484","DOIUrl":"10.1016/j.jhepr.2025.101484","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>High liver stiffness correlates with poor outcomes in hepatocellular carcinoma (HCC). Prior studies focused on neoplastic cells rather than the tumor microenvironment. This study investigated how the tumor microenvironment, particularly mechanosignaling in hepatic stellate cells (HSCs), drives HCC progression.</div></div><div><h3>Methods</h3><div>The study examined the roles of transglutaminase 2 (TGM2) and integrin β1 (ITGB1) in HSCs under mechanical stress through proteomics, cell contraction assays, and protein interactions. It also analyzed gene expression data from 178 patients with HCC and cirrhosis to assess the impact of TGM2 and ITGB1 on overall survival (OS). Mitochondrial transfer and cell migration were observed using confocal microscopy, and the effect of TGM2/ITGB1 on extracellular matrix (ECM) remodeling and HCC recurrence was studied in a rat liver cancer model.</div></div><div><h3>Results</h3><div>We showed that HSC activation under matrix stiffness relied on ITGB1 mechanosignaling, with high cell-surface TGM2 expression required for ITGB1 activation. This process activated downstream CAV1, which in turn stabilized ITGB1 expression. Moreover, high co-expression of TGM2/ITGB1 (R = 0.77, <em>p</em> &lt;2.2 × 10^-16) was negatively correlated with OS. Interestingly, we found massive mitochondrial transfer in hybrid co-cultures between cancer-associated fibroblasts (CAFs) and Huh7 cells by tunneling nanotubes under high stiffness (<em>p</em> = 0.0095), which appeared to be associated with TGM2/ITGB1. Huh7 cells with CAF-derived mitochondria exhibited enhanced migration under increased substrate stiffness (<em>p</em> &lt;0.0001). Accordingly, high liver stiffness activated CAFs, leading to ECM remodeling and postoperative recurrence of HCC. TGM2/ITGB1 was essential for matrix stiffness-driven HCC recurrence following surgery.</div></div><div><h3>Conclusions</h3><div>This study revealed a novel mechanism by which HSCs facilitate HCC progression under matrix stiffness, which may aid in the design of therapies for the clinical treatment of HCC.</div></div><div><h3>Impact and Implications</h3><div>Hepatic stellate cells (HSCs) undergo differentiation into cancer-associated fibroblasts (CAFs), which constitute the primary stromal cell population within the liver tumor microenvironment and are associated with poor prognosis in patients with hepatocellular cancer (HCC). The precise mechanisms through which CAFs facilitate HCC progression remain incompletely elucidated. In this study, we emphasize the role of transglutaminase 2-medated integrin β1 in the activation of HSCs induced by increased matrix stiffness. Furthermore, we explore how enhanced matrix stiffness promotes mitochondrial transfer, thereby facilitating the migration of HCC cells. These insights may inform the development of targeted therapeutic strategies for the clinical management of HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101484"},"PeriodicalIF":7.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096424","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":"Safety and efficacy of 24 weeks of pemvidutide in metabolic dysfunction-associated steatotic liver disease: A randomized, controlled clinical trial","authors":"Sarah K. Browne ,&nbsp;John J. Suschak ,&nbsp;Shaheen Tomah ,&nbsp;Julio A. Gutierrez ,&nbsp;Jay Yang ,&nbsp;Bertrand Georges ,&nbsp;M. Scot Roberts ,&nbsp;M. Scott Harris","doi":"10.1016/j.jhepr.2025.101483","DOIUrl":"10.1016/j.jhepr.2025.101483","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;This was a double-blind 12-week extension of a randomized, placebo-controlled, 12-week trial of pemvidutide, a glucagon-like peptide-1/glucagon dual receptor agonist, in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Completers of a double-blind trial of pemvidutide in MASLD, who were previously randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks, were offered an additional 12 weeks of treatment at their originally assigned dose for a total of 24 weeks of treatment. Participants were stratified by the presence or absence of type 2 diabetes mellitus (T2DM). The primary efficacy endpoint was relative reduction (%) from baseline in liver fat content by magnetic resonance imaging-proton density fat fraction after 24 weeks of treatment.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;There were 64 participants in the extension trial. Baseline mean values for BMI and liver fat content were 36.7 kg/m&lt;sup&gt;2&lt;/sup&gt; and 22.2%; 26.6% of participants had T2DM. After 24 weeks of treatment, pemvidutide achieved relative reductions in liver fat content from baseline of 56.3%, 75.2%, and 76.4% for the pemvidutide 1.2 mg, 1.8 mg, and 2.4 mg groups respectively, &lt;em&gt;vs.&lt;/em&gt; 14.0% for placebo (&lt;em&gt;p&lt;/em&gt; &lt;0.001 &lt;em&gt;vs.&lt;/em&gt; placebo, all treatment groups), with 84.6% of participants achieving 50% reductions in liver fat content and 53.8% achieving normalization (≤5% liver fat content) at the 1.8 mg dose. Body weight was also reduced by 6.2% (&lt;em&gt;p&lt;/em&gt; &lt;0.001 &lt;em&gt;vs.&lt;/em&gt; placebo) over 24 weeks of treatment. Pemvidutide was well-tolerated at all doses, with low incidences of side effects.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;In individuals with MASLD, 24 weeks of pemvidutide treatment resulted in significant reductions in liver fat content and body weight that further improved upon the effects observed at 12 weeks.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Overweight and obesity are strongly associated with metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), as the excess liver fat associated with obesity is a known driver of these conditions. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite, whereas G-coupled glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, providing a more potent mechanism for reducing liver fat content than weight loss alone. We previously showed that once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, significantly reduced liver fat content, hepatic inflammatory activity, and body weight over 12 weeks. The current trial demonstrates that continued treatment with pemvidutide further improves these clinical markers of M","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101483"},"PeriodicalIF":7.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218826","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":"Profiles of HBV DNA integration in humans with hepatitis B virus infection: Insights for antiviral treatment","authors":"Rex Wan-Hin Hui ,&nbsp;Danny Ka-Ho Wong ,&nbsp;Xueying Lyu ,&nbsp;Lung-Yi Mak ,&nbsp;James Fung ,&nbsp;Wai-Kay Seto ,&nbsp;Daniel Wai-Hung Ho ,&nbsp;Man-Fung Yuen","doi":"10.1016/j.jhepr.2025.101487","DOIUrl":"10.1016/j.jhepr.2025.101487","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>HBV integration profiles in the natural history of chronic HBV infection (CHB) have not been well-defined. Hence, we aimed to determine HBV integration profiles across different CHB phases.</div></div><div><h3>Methods</h3><div>We delineated integration profiles from liver biopsies of 55 patients in different CHB phases (3 HBsAg-positive/HBeAg-positive infection; 13 HBsAg-positive/HBeAg-positive hepatitis; 7 HBsAg-positive/HBeAg-negative infection; 12 HBsAg-positive/HBeAg-negative hepatitis; 10 HBsAg seroclearance; 10 occult HBV). Target-capture next-generation sequencing (NovaSeq-6000) was performed, and integrations were characterized on AVID (integrations defined as chimeric fusions in ≥1 soft-clipped reads and ≥2 total reads).</div></div><div><h3>Results</h3><div>HBV integrations were detected in 35 HBsAg-positive (100%), 8 (80%) HBsAg seroclearance, and 7 (70%) occult HBV patients, respectively. There was a stepwise decrease in integration events from HBsAg-positive/HBeAg-positive (median 9.6 [IQR 9.3-10.1] log integrations per liver), HBsAg-positive/HBeAg-negative (8.7 [8.4-9.0] log integrations) and HBsAg-negative patient groups (7.3 [6.8-7.7] log integrations) (<em>p &lt;</em>0.001 for trend). There were no differences in integration frequencies in chronic infection (ALT &lt; the upper limit of normal) and chronic hepatitis (ALT ≥ the upper limit of normal) for either HBeAg-positive or -negative patients (all <em>p</em> &gt;0.05). No significant differences in integration frequencies were noted between HBsAg seroclearance and occult HBV groups (<em>p</em> &gt;0.05). HBV genome integration breakpoints clustered around nucleotide 1800 in all disease phases. Human genome breakpoints were also delineated, and LINC00486 was the most frequently involved human gene in all disease phases.</div></div><div><h3>Conclusion</h3><div>We characterized the HBV DNA integration patterns and genome breakpoints of patients in different CHB disease phases. These findings enhance our understanding of the natural history of CHB.</div></div><div><h3>Impact and implications</h3><div>HBV integration profiles in the natural history of chronic HBV infection have not been well-defined. We utilized next-generation sequencing in a well-characterized cohort of patients with HBV at different disease phases, demonstrating a stepwise decrease in integration events as HBV progressed from HBeAg-positive to HBeAg-negative, and then to HBsAg-negative phases. Human and viral genome breakpoints were also identified. These findings enhance our understanding of the natural history of CHB, and provide insights for antiviral treatment.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"Article 101487"},"PeriodicalIF":7.5,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865931","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":"Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development.","authors":"Jonas Ghouse, Helene Gellert-Kristensen, Colm J O'Rourke, Anne-Sofie Seidelin, Gudmar Thorleifsson, Gardar Sveinbjörnsson, Vinicius Tragante, Chigoziri Konkwo, Joseph Brancale, Silvia Vilarinho, Tim M Eyrich, Gustav Ahlberg, Johan S Bundgaard, Søren A Rand, Pia R Lundegaard, Erik Sørensen, Christina Mikkelsen, Jacob Træholt, Christian Erikstrup, Khoa M Dinh, Mie T Bruun, Bitten Aa Jensen, Jakob T Bay, Søren Brunak, Karina Banasik, Henrik Ullum, Triin Laisk, Reedik Mägi, Lincoln D Nadauld, Kirk U Knowlton, Stacey Knight, Lise L Gluud, Kirsten Vistisen, Einar S Björnsson, Magnus O Ulfarsson, Patrick Sulem, Hilma Holm, Ole B Pedersen, Sisse R Ostrowski, Daniel F Gudbjartsson, Thorunn Rafnar, Kari Stefansson, Ulrik Lassen, Hans-Christian Pommergaard, Jens G Hillingsø, Jesper B Andersen, Henning Bundgaard, Stefan Stender","doi":"10.1016/j.jhepr.2025.101485","DOIUrl":"10.1016/j.jhepr.2025.101485","url":null,"abstract":"<p><strong>Background & aims: </strong>The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC.</p><p><strong>Methods: </strong>We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC.</p><p><strong>Results: </strong>In meta-analyses totaling 6,540 cases and 2,096,759 controls, we identified 10 associations with HCC, of which five (in <i>KLF15</i>, <i>HSD17B13</i>, <i>APOE</i>, <i>HFE</i>, and <i>MTARC1</i>) have not previously been implicated in HCC at genome-wide statistical significance. Known associations in <i>PNPLA3</i>, <i>TM6SF2</i>, <i>TERT</i>, <i>IFNL4</i>, and <i>HLA-DP1</i> were confirmed. All associations except <i>KLF15</i> were validated in independent cohorts totaling 7,630 cases and 733,689 controls. The largest per-allele effect was seen for <i>TM6SF2</i> (beta = 0.61) followed by <i>PNPLA3</i> (0.55), <i>HFE</i> (0.45), <i>IFNL4</i> (0.31), <i>APOE</i> (0.27), <i>HSD17B13</i>, <i>HLA-DP1</i>, and <i>TERT</i> (all 0.21), and <i>MTARC1</i> (0.17). The identified variants had comparable effects on incident HCC in individuals with prevalent obesity, a high alcohol intake, diabetes, or cirrhosis. Mendelian randomization analyses confirmed the causal role of obesity in HCC. We found strong correlations between genetic effects on HCC and hepatic steatosis (r² = 0.75), and HCC and cirrhosis (r² = 0.69), whereas only three loci (<i>APOE</i>, <i>HFE</i>, and <i>TERT</i>) had concordant effects on HCC and biliary tract cancer.</p><p><strong>Conclusions: </strong>We identified and validated nine genetic variants associated with an increased risk of HCC development.</p><p><strong>Impact and implications: </strong>The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"101485"},"PeriodicalIF":7.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873260","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}

{"title":"Plasma proteomic signature for preoperative prediction of microvascular invasion in HCC.","authors":"Xinrui Shi, Yunzheng Zhao, Ke Li, Qingyu Li, Yifeng Cui, Yuhang Sui, Liang Zhao, Haonan Zhou, Yongsheng Yang, Jiajun Li, Meng Zhou, Zhaoyang Lu","doi":"10.1016/j.jhepr.2025.101481","DOIUrl":"10.1016/j.jhepr.2025.101481","url":null,"abstract":"<p><strong>Background & aims: </strong>Microvascular invasion (MVI) is a major determinant of poor prognosis in hepatocellular carcinoma (HCC). However, reliable non-invasive biomarkers for the preoperative evaluation and diagnosis of MVI are urgently needed in clinical practice.</p><p><strong>Methods: </strong>Plasma samples were collected from 160 patients with HCC (80 MVI-positive and 80 MVI-negative) from four medical centers. Plasma proteomic profiling was obtained using data-independent acquisition mass spectrometry. Principal component analysis and differential protein abundance analysis were used to assess the proteomic changes between the two groups of patients. Protein biomarker candidates were further quantitatively validated by ELISA.</p><p><strong>Results: </strong>Proteomic analysis of 50 patients with HCC (25 MVI-positive and 25 MVI-negative) identified three plasma protein biomarkers (TALDO1, PDIA3, and PGK1) that are significantly upregulated in MVI-positive patients (FDR-adjusted <i>p</i> <0.05) and were subsequently cross-validated by ELISA. A machine learning-based <b>P</b>lasma p<b>R</b>otein MV<b>I</b> risk <b>M</b>odel (PRIM) was developed for the preoperative prediction of MVI. PRIM demonstrated excellent discriminatory ability, with areas under the receiver operating characteristic curve values ranging from 0.78 to 0.99 across three independent cohorts. Single-cell RNA sequencing of five HCC tumors provided a cell type-resolved atlas of biomarker expression, showing their predominant presence in malignant cells and macrophages within the MVI-positive tumor microenvironment compared with MVI-negative tumors.</p><p><strong>Conclusions: </strong>This study provides a comprehensive analysis of the plasma proteomic landscape in HCC and presents a promising blood-based tool for preoperative MVI risk stratification.</p><p><strong>Impact and implications: </strong>This study highlights the transformative potential of plasma proteomic profiling in improving the preoperative prediction of microvascular invasion in hepatocellular carcinoma (HCC). By integrating data-independent acquisition mass spectrometry and machine learning, we identified three plasma protein biomarkers (TALDO1, PDIA3, and PGK1) and developed the Plasma pRotein MVI risk Model (PRIM), which demonstrated robust diagnostic accuracy across multicenter validation cohorts. These findings pave the way for preoperative risk stratification and personalized therapeutic strategies in HCC management.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"101481"},"PeriodicalIF":7.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873265","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}

{"title":"GDF15 is associated with hepatocellular senescence and correlates with mortality in patients with alcohol-associated hepatitis","authors":"Teresa Rubio-Tomás ,&nbsp;David Martí-Aguado ,&nbsp;Delia Blaya ,&nbsp;Silvia Ariño ,&nbsp;Beatriz Aguilar-Bravo ,&nbsp;Raquel A. Martínez García de la Torre ,&nbsp;Marc Miravet-Marti ,&nbsp;Raquel Ferrer-Lorente ,&nbsp;Laura Zanatto ,&nbsp;Zengqing Xu ,&nbsp;Laura Garcia-Tercero ,&nbsp;Carlos Mateos-Sánchez ,&nbsp;Juan José Lozano ,&nbsp;Isabella Dotti ,&nbsp;Johanne Poisson ,&nbsp;Marion Tanguy ,&nbsp;Azucena Salas ,&nbsp;Pierre-Emmanuel Rautou ,&nbsp;Ramon Bataller ,&nbsp;Pau Sancho-Bru","doi":"10.1016/j.jhepr.2025.101478","DOIUrl":"10.1016/j.jhepr.2025.101478","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cellular senescence is characterized by the loss of proliferative capacity, cell cycle arrest, and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP). Senescence is frequently present in advanced chronic liver diseases; however, the impact of hepatocellular senescence in alcohol-associated liver disease (ALD) progression and alcohol-associated hepatitis (AH) is poorly understood.</div></div><div><h3>Methods</h3><div>Senescence was evaluated in transcriptomic data from patients at different ALD stages: advanced fibrosis (n = 10), cirrhosis (n = 10), and AH (n = 29). Plasma GDF15 levels were tested in patients with AH (n = 68), compensated cirrhosis (n = 15), heavy drinkers without liver disease (n = 15), and healthy controls (n = 10). Results were confirmed in an independent validation cohort.</div></div><div><h3>Results</h3><div>Transcriptomic analysis revealed an increased expression of senescence-associated genes and an enrichment of SASP gene signatures in patients with cirrhosis and particularly with AH. The association of senescence with AH was confirmed by p21 staining and the expression of senescence markers (<em>i.e</em>. CDKN1A, CDKN2A, CDKN2B, IL6, and SERPINE1), which positively correlated with clinical severity scores. Among the SASP factors, GDF15 was expressed in the hepatocytes of patients with AH and was strongly associated with senescence markers. Circulating GDF15 levels were specifically increased in patients with AH and positively correlated with severity scores. Moreover, plasma GDF15 levels predicted the response to corticosteroids and 90-day mortality in two independent cohorts of patients with AH.</div></div><div><h3>Conclusions</h3><div>These results suggest that AH is characterized by the presence of hepatocellular senescence and elevated circulating levels of SASP factors, particularly GDF15, which correlates with patients’ poor outcomes. This suggests that senescence may be both a player in AH pathogenesis and a potential biomarker for AH.</div></div><div><h3>Impact and implications</h3><div>The pathogenesis of alcohol-associated liver disease (ALD) and hepatitis (AH) remains to be fully elucidated, and there is a need for biomarkers that can effectively monitor disease progression and assess patient response to therapy. In this study, we show the association of AH with hepatocellular senescence and the hepatic expression of senescence-associated secretory phenotype (SASP) factors, which correlate with poor patient outcome. Furthermore, we provide evidence that SASP factors such as GDF15 may be potential plasma biomarkers for AH. The findings of this study lay the groundwork for future research into the role of senescence in the pathogenesis of AH, as well as into the potential use of senescence and SASP-related molecules as biomarkers for AH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"Article 101478"},"PeriodicalIF":7.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749594","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}