Pub Date : 2025-09-24DOI: 10.1016/j.jhepr.2025.101602
Haixiang Zheng , Kuangyi Wu , Hong Zheng , Guanlin Chen , Yulong Lan , Shuohua Chen , Gavino Casu , Leonardo Antonio Sechi , Shouling Wu , Gianpaolo Vidili , Youren Chen
<div><h3>Background & Aims</h3><div>The correlation between systemic inflammation response index (SIRI) and both cardiovascular disease (CVD, including myocardial infarction and total stroke) and mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. We examined this association in a large Chinese cohort.</div></div><div><h3>Methods</h3><div>A population of 24,340 patients with MASLD from the Kailuan study were observed over a median of 16.0 years. SIRI was calculated based on neutrophil, monocyte, and lymphocyte counts. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CVD and mortality across SIRI quartiles. Net reclassification improvement assessed SIRI’s predictive value <em>vs.</em> high-sensitivity C-reactive protein and other indices. Mediation analysis assessed the roles of platelet count (PLT), Chinese visceral adiposity index and triglyceride-glucose index.</div></div><div><h3>Results</h3><div>During follow-up, 4,171 CVD events and 4,510 deaths occurred. Elevated SIRI was significantly linked to higher risks of CVD (HR for Q4 <em>vs.</em> Q1 1.21; 95% CI 1.10–1.31; <em>p <</em>0.001), including myocardial infarction (HR 1.22; 95% CI 1.01–1.48; <em>p</em> = 0.045), total stroke (HR 1.18; 95% CI 1.06–1.31; <em>p</em> = 0.003), and mortality (HR 1.34; 95% CI 1.24–1.46; <em>p <</em>0.001) in MASLD. Associations were stronger among women (HR 1.17; 95% CI 1.07–1.29; <em>p <</em>0.01) and physically inactive individuals (HR 1.09; 95% CI 1.05–1.13; <em>p <</em>0.01). SIRI improved outcome prediction over high-sensitivity C-reactive protein and other indices, with significant reclassification gains (5.84; 95% CI 2.57–9.12; <em>p <</em>0.001). Triglyceride-glucose index partially mediated these associations (5.3% for CVD, <em>p</em> = 0.006; 2.9% for mortality, <em>p</em> = 0.003), whereas PLT exhibited a slight inverse mediation effect on mortality (-3.3%, <em>p</em> = 0.032).</div></div><div><h3>Conclusions</h3><div>High SIRI independently correlates with increased risk of CVD and mortality in MASLD. These findings highlight the role of systemic inflammation and support SIRI as a potential biomarker for risk stratification in these individuals.</div></div><div><h3>Impact and implications</h3><div>This study provides important evidence linking systemic inflammation, as measured by the systemic inflammation response index, to increased cardiovascular disease and mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent condition with rising global burden. The findings underscore the clinical relevance of inflammation markers in cardiovascular risk stratification, particularly for patients and healthcare providers managing MASLD. Physicians and policymakers could incorporate systemic inflammation response index into routine assessments to identify patients with MASLD at higher risk of cardiovascu
背景和目的在代谢功能障碍相关脂肪变性肝病（MASLD）患者中，全身性炎症反应指数（SIRI）与心血管疾病（CVD，包括心肌梗死和全卒中）和死亡率之间的相关性尚不清楚。我们在一个庞大的中国队列中检验了这种关联。方法对来自开滦研究的24340例MASLD患者进行了中位数为16.0年的观察。SIRI是根据中性粒细胞、单核细胞和淋巴细胞计数计算的。Cox比例风险模型用于估计SIRI四分位数中心血管疾病和死亡率的风险比（hr）。净重分类改进评估了SIRI与高灵敏度c反应蛋白和其他指标的预测价值。中介分析评估血小板计数（PLT），中国内脏脂肪指数和甘油三酯-葡萄糖指数的作用。结果随访期间共发生4171例CVD事件和4510例死亡。SIRI升高与心血管疾病的高风险显著相关（第4季度的风险比为1.21;95% CI 1.10-1.31; p <0.001），包括心肌梗死（HR 1.22; 95% CI 1.01-1.48; p = 0.045）、总卒中（HR 1.18; 95% CI 1.06-1.31; p = 0.003）和MASLD的死亡率（HR 1.34; 95% CI 1.24-1.46; p <0.001）。女性（HR 1.17; 95% CI 1.07-1.29; p <0.01）和不爱运动的个体（HR 1.09; 95% CI 1.05-1.13; p <0.01）的相关性更强。SIRI改善了对高灵敏度c反应蛋白和其他指标的预后预测，具有显著的再分类增益（5.84;95% CI 2.57-9.12; p <0.001）。甘油三酯-葡萄糖指数部分介导了这些关联（心血管疾病5.3%,p = 0.006；死亡率2.9%,p = 0.003），而PLT对死亡率表现出轻微的反向中介作用（-3.3%,p = 0.032）。结论高SIRI与MASLD患者CVD风险和死亡率增加独立相关。这些发现强调了全身性炎症的作用，并支持SIRI作为这些个体风险分层的潜在生物标志物。影响和意义本研究提供了重要的证据，表明全身性炎症反应指数与代谢功能障碍相关的脂肪变性肝病（MASLD）患者心血管疾病和死亡率增加有关，MASLD是一种全球负担不断增加的普遍疾病。研究结果强调了炎症标志物在心血管风险分层中的临床相关性，特别是对于管理MASLD的患者和医疗保健提供者。医生和决策者可以将全身性炎症反应指数纳入常规评估，以识别心血管事件高风险的MASLD患者，潜在地指导旨在减轻全身性炎症和代谢功能障碍的有针对性的干预措施。然而，由于主要是来自中国北方的以社区为基础的男性队列，在广泛的临床应用之前，有必要对不同人群进行进一步的研究来证实这些关联。临床试验编号chictr - tnc -11001489。
{"title":"High systemic inflammation response index and increased cardiovascular risk and mortality in MASLD: A prospective cohort study","authors":"Haixiang Zheng , Kuangyi Wu , Hong Zheng , Guanlin Chen , Yulong Lan , Shuohua Chen , Gavino Casu , Leonardo Antonio Sechi , Shouling Wu , Gianpaolo Vidili , Youren Chen","doi":"10.1016/j.jhepr.2025.101602","DOIUrl":"10.1016/j.jhepr.2025.101602","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The correlation between systemic inflammation response index (SIRI) and both cardiovascular disease (CVD, including myocardial infarction and total stroke) and mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. We examined this association in a large Chinese cohort.</div></div><div><h3>Methods</h3><div>A population of 24,340 patients with MASLD from the Kailuan study were observed over a median of 16.0 years. SIRI was calculated based on neutrophil, monocyte, and lymphocyte counts. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CVD and mortality across SIRI quartiles. Net reclassification improvement assessed SIRI’s predictive value <em>vs.</em> high-sensitivity C-reactive protein and other indices. Mediation analysis assessed the roles of platelet count (PLT), Chinese visceral adiposity index and triglyceride-glucose index.</div></div><div><h3>Results</h3><div>During follow-up, 4,171 CVD events and 4,510 deaths occurred. Elevated SIRI was significantly linked to higher risks of CVD (HR for Q4 <em>vs.</em> Q1 1.21; 95% CI 1.10–1.31; <em>p <</em>0.001), including myocardial infarction (HR 1.22; 95% CI 1.01–1.48; <em>p</em> = 0.045), total stroke (HR 1.18; 95% CI 1.06–1.31; <em>p</em> = 0.003), and mortality (HR 1.34; 95% CI 1.24–1.46; <em>p <</em>0.001) in MASLD. Associations were stronger among women (HR 1.17; 95% CI 1.07–1.29; <em>p <</em>0.01) and physically inactive individuals (HR 1.09; 95% CI 1.05–1.13; <em>p <</em>0.01). SIRI improved outcome prediction over high-sensitivity C-reactive protein and other indices, with significant reclassification gains (5.84; 95% CI 2.57–9.12; <em>p <</em>0.001). Triglyceride-glucose index partially mediated these associations (5.3% for CVD, <em>p</em> = 0.006; 2.9% for mortality, <em>p</em> = 0.003), whereas PLT exhibited a slight inverse mediation effect on mortality (-3.3%, <em>p</em> = 0.032).</div></div><div><h3>Conclusions</h3><div>High SIRI independently correlates with increased risk of CVD and mortality in MASLD. These findings highlight the role of systemic inflammation and support SIRI as a potential biomarker for risk stratification in these individuals.</div></div><div><h3>Impact and implications</h3><div>This study provides important evidence linking systemic inflammation, as measured by the systemic inflammation response index, to increased cardiovascular disease and mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent condition with rising global burden. The findings underscore the clinical relevance of inflammation markers in cardiovascular risk stratification, particularly for patients and healthcare providers managing MASLD. Physicians and policymakers could incorporate systemic inflammation response index into routine assessments to identify patients with MASLD at higher risk of cardiovascu","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101602"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517868","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 : 2025-09-23DOI: 10.1016/j.jhepr.2025.101595
Pasquale Lombardi , Jung Sun Kim , Giulia F. Manfredi , Ciro Celsa , Claudia A.M. Fulgenzi , Antonio D’Alessio , Bernardo Stefanini , Niraj C. Doshi , Emily Warmington , Thomas U. Marron , Matthias Pinter , Bernhard Scheiner , Beodeul Kang , Ho Yeong Lim , Wei-Fan Hsu , Brooke Wietharn , Marianna Silletta , Alessandro Parisi , Chun-Yen Lin , Andrea Dalbeni , David J. Pinato
<div><h3>Background & Aims</h3><div>Atezolizumab plus bevacizumab (A+B) is a standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, optimal sequencing strategies after A+B failure remain undefined.</div></div><div><h3>Methods</h3><div>LEVIATHAN is a multicentre, observational study evaluating efficacy and survival outcomes in patients who progressed on A+B and subsequently received either lenvatinib or sorafenib as second-line therapy. Of 1,210 patients treated with first-line A+B between May 2018 and August 2024, 230 eligible patients were included (lenvatinib, n = 125 [54.3%]; sorafenib, n = 105 [45.7%]). Propensity score matching was applied to adjust for baseline imbalances, incorporating independent predictors of overall survival (OS) and response to prior treatment.</div></div><div><h3>Results</h3><div>In the overall second-line cohort, lenvatinib was associated with superior median progression-free survival (5.5 <em>vs.</em> 2.6 months, hazard ratio [HR] 0.41, <em>p</em> <0.001) and median OS (11.9 <em>vs.</em> 7.4 months, HR 0.67, <em>p</em> = 0.018) compared to sorafenib. From the start of A+B, the A+B-lenvatinib sequence achieved a median OS of 22.4 months <em>vs.</em> 14.3 months with A+B-sorafenib (HR 0.54, <em>p</em> <0.001). These differences persisted in the propensity score-matched cohort (median OS: 19.6 <em>vs.</em> 13.9 months, HR 0.67, <em>p</em> = 0.024). Multivariate analysis identified treatment with lenvatinib as an independent predictor of improved OS alongside alpha-fetoprotein ≤400 ng/ml, neutrophil-to-lymphocyte ratio <3, and absence of portal vein thrombosis.</div></div><div><h3>Conclusions</h3><div>The LEVIATHAN study supports lenvatinib as a more effective second-line option than sorafenib following A+B in unresectable HCC, including in patients with primary resistance to immunotherapy. While limited by the observational study design, these findings highlight the importance of treatment sequencing to optimise outcomes in advanced HCC.</div></div><div><h3>Impact and implications</h3><div>Continuing active treatment after progression on frontline atezolizumab plus bevacizumab (A+B) can benefit patients with advanced hepatocellular carcinoma (HCC), but evidence to guide second-line therapy remains limited. The LEVIATHAN study addresses this gap by evaluating real-world outcomes in a large, prospective, multinational cohort treated with lenvatinib or sorafenib after A+B discontinuation. Our findings show that lenvatinib provides significantly longer progression-free and overall survival than sorafenib, even after adjusting for baseline imbalances with propensity scores. Lenvatinib also achieved higher disease control rates, including in patients with primary resistance to immunotherapy. These results challenge the assumption that all VEGFR-targeting TKIs are equivalent post-ICI and suggest lenvatinib may be superior to sorafenib following anti-VEGF–based immunotherapy
背景：AimsAtezolizumab + bevacizumab （A+B）是不可切除肝细胞癌（HCC）的标准一线全身治疗。然而，A+B失败后的最佳测序策略仍未确定。sleviathan是一项多中心观察性研究，评估a +B治疗进展并随后接受lenvatinib或sorafenib作为二线治疗的患者的疗效和生存结果。在2018年5月至2024年8月期间接受一线A+B治疗的1210例患者中，纳入230例符合条件的患者（lenvatinib, n = 125[54.3%]；索拉非尼，n = 105[45.7%]）。采用倾向评分匹配来调整基线失衡，结合总生存期（OS）和对既往治疗反应的独立预测因子。结果在整个二线队列中，lenvatinib与索拉非尼相比具有更高的中位无进展生存期（5.5个月vs 2.6个月，风险比[HR] 0.41, p <0.001）和中位OS（11.9个月vs 7.4个月，HR 0.67, p = 0.018）。从A+B开始，A+B-lenvatinib序列的中位OS为22.4个月，而A+B-索拉非尼组为14.3个月（HR 0.54, p <0.001）。这些差异在倾向评分匹配的队列中持续存在（中位生存期：19.6 vs 13.9个月，HR 0.67, p = 0.024）。多变量分析发现lenvatinib治疗与甲胎蛋白≤400ng /ml、中性粒细胞与淋巴细胞比率<；3和门静脉血栓的消失一起是改善OS的独立预测因素。利维坦研究支持lenvatinib作为不可切除HCC（包括对免疫治疗有原发性耐药的患者）a +B后更有效的二线选择。虽然受到观察性研究设计的限制，但这些发现强调了治疗排序对优化晚期HCC预后的重要性。影响和意义一线atezolizumab + bevacizumab （A+B）进展后继续积极治疗可使晚期肝细胞癌（HCC）患者受益，但指导二线治疗的证据仍然有限。LEVIATHAN研究通过评估a +B停药后lenvatinib或sorafenib治疗的大型前瞻性多国队列的实际结果，解决了这一差距。我们的研究结果表明，lenvatinib比sorafenib提供了更长的无进展生存期和总生存期，即使在调整了倾向评分的基线不平衡后也是如此。Lenvatinib也实现了更高的疾病控制率，包括对免疫治疗的原发性耐药患者。这些结果挑战了所有靶向vegfr的TKIs在ici后相同的假设，并表明lenvatinib可能优于基于抗vegf的免疫治疗的索拉非尼。虽然仍需要前瞻性随机试验，但这些真实世界的数据为临床医生提供了有价值的指导，并有助于改进晚期HCC的治疗顺序。
{"title":"Lenvatinib vs. sorafenib as second-line treatment post atezolizumab plus bevacizumab for hepatocellular carcinoma: The LEVIATHAN study","authors":"Pasquale Lombardi , Jung Sun Kim , Giulia F. Manfredi , Ciro Celsa , Claudia A.M. Fulgenzi , Antonio D’Alessio , Bernardo Stefanini , Niraj C. Doshi , Emily Warmington , Thomas U. Marron , Matthias Pinter , Bernhard Scheiner , Beodeul Kang , Ho Yeong Lim , Wei-Fan Hsu , Brooke Wietharn , Marianna Silletta , Alessandro Parisi , Chun-Yen Lin , Andrea Dalbeni , David J. Pinato","doi":"10.1016/j.jhepr.2025.101595","DOIUrl":"10.1016/j.jhepr.2025.101595","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Atezolizumab plus bevacizumab (A+B) is a standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, optimal sequencing strategies after A+B failure remain undefined.</div></div><div><h3>Methods</h3><div>LEVIATHAN is a multicentre, observational study evaluating efficacy and survival outcomes in patients who progressed on A+B and subsequently received either lenvatinib or sorafenib as second-line therapy. Of 1,210 patients treated with first-line A+B between May 2018 and August 2024, 230 eligible patients were included (lenvatinib, n = 125 [54.3%]; sorafenib, n = 105 [45.7%]). Propensity score matching was applied to adjust for baseline imbalances, incorporating independent predictors of overall survival (OS) and response to prior treatment.</div></div><div><h3>Results</h3><div>In the overall second-line cohort, lenvatinib was associated with superior median progression-free survival (5.5 <em>vs.</em> 2.6 months, hazard ratio [HR] 0.41, <em>p</em> <0.001) and median OS (11.9 <em>vs.</em> 7.4 months, HR 0.67, <em>p</em> = 0.018) compared to sorafenib. From the start of A+B, the A+B-lenvatinib sequence achieved a median OS of 22.4 months <em>vs.</em> 14.3 months with A+B-sorafenib (HR 0.54, <em>p</em> <0.001). These differences persisted in the propensity score-matched cohort (median OS: 19.6 <em>vs.</em> 13.9 months, HR 0.67, <em>p</em> = 0.024). Multivariate analysis identified treatment with lenvatinib as an independent predictor of improved OS alongside alpha-fetoprotein ≤400 ng/ml, neutrophil-to-lymphocyte ratio <3, and absence of portal vein thrombosis.</div></div><div><h3>Conclusions</h3><div>The LEVIATHAN study supports lenvatinib as a more effective second-line option than sorafenib following A+B in unresectable HCC, including in patients with primary resistance to immunotherapy. While limited by the observational study design, these findings highlight the importance of treatment sequencing to optimise outcomes in advanced HCC.</div></div><div><h3>Impact and implications</h3><div>Continuing active treatment after progression on frontline atezolizumab plus bevacizumab (A+B) can benefit patients with advanced hepatocellular carcinoma (HCC), but evidence to guide second-line therapy remains limited. The LEVIATHAN study addresses this gap by evaluating real-world outcomes in a large, prospective, multinational cohort treated with lenvatinib or sorafenib after A+B discontinuation. Our findings show that lenvatinib provides significantly longer progression-free and overall survival than sorafenib, even after adjusting for baseline imbalances with propensity scores. Lenvatinib also achieved higher disease control rates, including in patients with primary resistance to immunotherapy. These results challenge the assumption that all VEGFR-targeting TKIs are equivalent post-ICI and suggest lenvatinib may be superior to sorafenib following anti-VEGF–based immunotherapy","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101595"},"PeriodicalIF":7.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518450","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 : 2025-09-23DOI: 10.1016/j.jhepr.2025.101599
Ahmed Ghallab , Maiju Myllys , Daniela González , Adrian Friebel , Zaynab Hobloss , Reham Hassan , Hannah Schmidt , Qasim Siddiqui , Deng Zhipeng , Rama Hendawi , Brigitte Begher-Tibbe , Joerg Reinders , Katharina Derksen , Ute Hofmann , Julia C. Duda , Lucia Ameis , Kathrin Möllenhoff , Abdellatief Seddek , Noha Abdelmageed , Ellen Strängberg , Jan G. Hengstler
Background & Aims
Cholemic nephropathy (CN) is a severe complication of liver diseases associated with cholestasis and represents an unmet medical need. Recently, we identified the molecular mechanism of CN and showed that the systemic apical sodium-dependent bile acid transporter inhibitor (ASBTi) AS0369 prevented CN in mice. However, it is not clear if ASBTi is effective in a therapeutic rather than a preventive setting.
Methods
AS0369 was administered daily for 4 weeks to bile duct-ligated (BDL) mice at four CN stages: (1) early stage with proximal tubular epithelial cell (pTEC) death (BDL-day 3); (2) inflammation, leaky peritubular capillaries, and tubular dilatation (BDL-day 21); (3) fibrosis (BDL-day 42); and (4) advanced stage with glomerular cysts (BDL-day 63). Disease progression was evaluated by biochemical, histopathological, and RNA-sequencing analysis.
Results
ASBTi increased urinary excretion of bile acids (BAs) and reciprocally reduced BA concentrations in blood and renal tissue at all disease stages. Therapeutic efficacy was highest when ASBTi was given at early disease stages, e.g. urinary BA excretion was increased 9-fold (p <0.001) at the early stage compared to 4-fold (p = 0.021) at the late stage. ASBTi reduced the pTEC injury biomarker KIM-1, tissue damage, replacement proliferation, peritubular capillary damage and renal fibrosis. Additionally, late-stage disease features, such as glomerular cysts, were ameliorated (46% at the late stage, p = 0.005) by the ASBTi. RNA-sequencing revealed that ASBTi attenuated BDL-induced gene deregulation at all stages, with a larger effect size at early stages.
Conclusions
Early systemic ASBTi therapy, initiated at the onset of pTEC death, provides the greatest therapeutic benefit. Nonetheless, even at later stages, ASBTi can ameliorate features of advanced CN.
Impact and implications
This study demonstrates that systemic inhibition of the apical sodium-dependent bile acid transporter (ASBTi) alleviates cholemic nephropathy across disease stages in a bile duct ligation mouse model. The greatest benefit was achieved when treatment was initiated early, coinciding with proximal tubular epithelial cell death, but even advanced features such as glomerular cysts were partially reversed. These findings highlight ASBTi as a promising therapeutic strategy for cholemic nephropathy, addressing a major unmet need in cholestatic liver disease. By targeting bile acid accumulation and related injury pathways, ASBTi may improve renal outcomes and broaden treatment options in affected patients.
{"title":"Stage-dependent effects of systemic ASBT inhibition in a cholestasis-induced cholemic nephropathy mouse model","authors":"Ahmed Ghallab , Maiju Myllys , Daniela González , Adrian Friebel , Zaynab Hobloss , Reham Hassan , Hannah Schmidt , Qasim Siddiqui , Deng Zhipeng , Rama Hendawi , Brigitte Begher-Tibbe , Joerg Reinders , Katharina Derksen , Ute Hofmann , Julia C. Duda , Lucia Ameis , Kathrin Möllenhoff , Abdellatief Seddek , Noha Abdelmageed , Ellen Strängberg , Jan G. Hengstler","doi":"10.1016/j.jhepr.2025.101599","DOIUrl":"10.1016/j.jhepr.2025.101599","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Cholemic nephropathy (CN) is a severe complication of liver diseases associated with cholestasis and represents an unmet medical need. Recently, we identified the molecular mechanism of CN and showed that the systemic apical sodium-dependent bile acid transporter inhibitor (ASBTi) AS0369 prevented CN in mice. However, it is not clear if ASBTi is effective in a therapeutic rather than a preventive setting.</div></div><div><h3>Methods</h3><div>AS0369 was administered daily for 4 weeks to bile duct-ligated (BDL) mice at four CN stages: (1) early stage with proximal tubular epithelial cell (pTEC) death (BDL-day 3); (2) inflammation, leaky peritubular capillaries, and tubular dilatation (BDL-day 21); (3) fibrosis (BDL-day 42); and (4) advanced stage with glomerular cysts (BDL-day 63). Disease progression was evaluated by biochemical, histopathological, and RNA-sequencing analysis.</div></div><div><h3>Results</h3><div>ASBTi increased urinary excretion of bile acids (BAs) and reciprocally reduced BA concentrations in blood and renal tissue at all disease stages. Therapeutic efficacy was highest when ASBTi was given at early disease stages, <em>e.g</em>. urinary BA excretion was increased 9-fold (<em>p</em> <0.001) at the early stage compared to 4-fold (<em>p</em> = 0.021) at the late stage. ASBTi reduced the pTEC injury biomarker KIM-1, tissue damage, replacement proliferation, peritubular capillary damage and renal fibrosis. Additionally, late-stage disease features, such as glomerular cysts, were ameliorated (46% at the late stage, <em>p</em> = 0.005) by the ASBTi. RNA-sequencing revealed that ASBTi attenuated BDL-induced gene deregulation at all stages, with a larger effect size at early stages.</div></div><div><h3>Conclusions</h3><div>Early systemic ASBTi therapy, initiated at the onset of pTEC death, provides the greatest therapeutic benefit. Nonetheless, even at later stages, ASBTi can ameliorate features of advanced CN.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that systemic inhibition of the apical sodium-dependent bile acid transporter (ASBTi) alleviates cholemic nephropathy across disease stages in a bile duct ligation mouse model. The greatest benefit was achieved when treatment was initiated early, coinciding with proximal tubular epithelial cell death, but even advanced features such as glomerular cysts were partially reversed. These findings highlight ASBTi as a promising therapeutic strategy for cholemic nephropathy, addressing a major unmet need in cholestatic liver disease. By targeting bile acid accumulation and related injury pathways, ASBTi may improve renal outcomes and broaden treatment options in affected patients.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101599"},"PeriodicalIF":7.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517865","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 : 2025-09-22DOI: 10.1016/j.jhepr.2025.101584
Facai Yang , Anfeng Si , Cheng Chi , Weihu Ma , Yinmin Gu , Yongbo Pan , Jingzhan Zhu , Yigang He , Xuewu Tang , Qiushi Yu , Yanuo Chen , Tongfeng Liu , Shan Gao , Fangliang Xie , Zhengqing Lei , Hongping Xia , Zhangjun Cheng
Background & Aims
N6-methyladenosine (m6A) modification regulates mRNA stability and translation to promote cancer progression. FK506-binding protein 9 (FKBP9), a peptidyl-prolyl isomerase, is associated with carcinogenesis, but its role in m6A modification remains unclear. In this study we aimed to explore how FKBP9 regulates m6A modification during the development of hepatocellular carcinoma (HCC).
Methods
The expression of FKBP9 in HCC was profiled by reverse-transcription quantitative PCR, western blot, ELISA, and immunohistochemistry. Cell proliferation, migration, invasion, apoptosis, and mRNA stability were examined using CCK-8, colony formation, flow cytometry, and cycloheximide treatment. An orthotopic allograft tumor model was constructed for in vivo analysis. Immunoprecipitation, mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing were performed to elucidate underlying mechanisms.
Results
FKBP9 was significantly upregulated in both HCC tissues and serum (p <0.05) and correlated with unfavorable clinical outcomes in patients (p <0.05). Its overexpression enhanced HCC cell proliferation and metastasis, while its depletion triggered cell cycle arrest and apoptosis. Mechanistically, FKBP9 interacted with the KH3-4 domains of IGF2BP1 through its peptidyl-prolyl isomerase domain, thereby stabilizing the binding of IGF2BP1 to m6A-modified MYC and PDGFB. Clinical analysis further confirmed that FKBP9 expression was positively associated with the expression of MYC and PDGFB at both the mRNA and protein levels (p <0.05). Co-overexpression of FKBP9 with MYC or PDGFB was linked to a worse prognosis (p <0.05).
Conclusions
FKBP9 promotes HCC progression by facilitating IGF2BP1 recognition of m6A-modified transcripts, thereby stabilizing MYC and PDGFB. The FKBP9–IGF2BP1 axis represents a potential therapeutic target in HCC.
Impact and implications
This study highlights the critical role of FKBP9 in hepatocellular carcinoma progression by regulating IGF2BP1-mediated m6A RNA recognition, thereby enhancing the stability of key oncogenic transcripts such as MYC and PDGFB. These findings provide new insights into the molecular mechanisms driving hepatocellular carcinoma and identify potential therapeutic opportunities for patients with poor prognosis linked to high FKBP9 expression. The FKBP9–IGF2BP1 axis may serve as both a biomarker and a therapeutic target to guide the development of new treatment strategies. Further studies are warranted to validate these results in larger patient cohorts and to assess the clinical feasibility of targeting this pathway.
{"title":"FKBP9 enhances IGF2BP1-mediated m6A recognition to promote hepatocellular carcinoma progression","authors":"Facai Yang , Anfeng Si , Cheng Chi , Weihu Ma , Yinmin Gu , Yongbo Pan , Jingzhan Zhu , Yigang He , Xuewu Tang , Qiushi Yu , Yanuo Chen , Tongfeng Liu , Shan Gao , Fangliang Xie , Zhengqing Lei , Hongping Xia , Zhangjun Cheng","doi":"10.1016/j.jhepr.2025.101584","DOIUrl":"10.1016/j.jhepr.2025.101584","url":null,"abstract":"<div><h3>Background & Aims</h3><div>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification regulates mRNA stability and translation to promote cancer progression. FK506-binding protein 9 (FKBP9), a peptidyl-prolyl isomerase, is associated with carcinogenesis, but its role in m<sup>6</sup>A modification remains unclear. In this study we aimed to explore how FKBP9 regulates m<sup>6</sup>A modification during the development of hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>The expression of FKBP9 in HCC was profiled by reverse-transcription quantitative PCR, western blot, ELISA, and immunohistochemistry. Cell proliferation, migration, invasion, apoptosis, and mRNA stability were examined using CCK-8, colony formation, flow cytometry, and cycloheximide treatment. An orthotopic allograft tumor model was constructed for <em>in vivo</em> analysis. Immunoprecipitation, mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing were performed to elucidate underlying mechanisms.</div></div><div><h3>Results</h3><div>FKBP9 was significantly upregulated in both HCC tissues and serum (<em>p</em> <0.05) and correlated with unfavorable clinical outcomes in patients (<em>p</em> <0.05). Its overexpression enhanced HCC cell proliferation and metastasis, while its depletion triggered cell cycle arrest and apoptosis. Mechanistically, FKBP9 interacted with the KH3-4 domains of IGF2BP1 through its peptidyl-prolyl isomerase domain, thereby stabilizing the binding of IGF2BP1 to m<sup>6</sup>A-modified <em>MYC</em> and <em>PDGFB</em>. Clinical analysis further confirmed that FKBP9 expression was positively associated with the expression of MYC and PDGFB at both the mRNA and protein levels (<em>p</em> <0.05). Co-overexpression of FKBP9 with MYC or PDGFB was linked to a worse prognosis (<em>p</em> <0.05).</div></div><div><h3>Conclusions</h3><div>FKBP9 promotes HCC progression by facilitating IGF2BP1 recognition of m6A-modified transcripts, thereby stabilizing MYC and PDGFB. The FKBP9–IGF2BP1 axis represents a potential therapeutic target in HCC.</div></div><div><h3>Impact and implications</h3><div>This study highlights the critical role of FKBP9 in hepatocellular carcinoma progression by regulating IGF2BP1-mediated m6A RNA recognition, thereby enhancing the stability of key oncogenic transcripts such as <em>MYC</em> and <em>PDGFB</em>. These findings provide new insights into the molecular mechanisms driving hepatocellular carcinoma and identify potential therapeutic opportunities for patients with poor prognosis linked to high FKBP9 expression. The FKBP9–IGF2BP1 axis may serve as both a biomarker and a therapeutic target to guide the development of new treatment strategies. Further studies are warranted to validate these results in larger patient cohorts and to assess the clinical feasibility of targeting this pathway.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101584"},"PeriodicalIF":7.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145464822","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 : 2025-09-20DOI: 10.1016/j.jhepr.2025.101598
Sigurd Breder , Christina Villard , Emma Eide , Benny Wang , Lise Katrine Engesæter , Henrik Mikael Reims , Johannes Roksund Hov , Espen Melum , Lars Aabakken , Pål Dag Line , Jon Lømo , Krzyztof Grzyb , Kristine Wiencke , Annika Bergquist , Trine Folseraas
Background & Aims
Liver transplantation (LT) to prevent cholangiocarcinoma (CCA) in individuals with primary sclerosing cholangitis (PSC) and bile duct dysplasia was introduced in Norway and Sweden in the early 2000s. We aimed to evaluate this practice to potentially improve future selection of candidates for LT.
Methods
We conducted a retrospective study of 512 adults with PSC who underwent first-time LT between 2000–2021 at Oslo and Karolinska University Hospitals. Pre-LT findings in bile duct brush cytology and/or biopsy of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) were compared with histological findings in the explanted livers and survival rates were assessed.
Results
Bile duct dysplasia, low-grade (LGD) or high-grade (HGD), was the primary LT indication in 17% (88/512). Among individuals transplanted for LGD, only 10% (3/29) had HGD or CCA in the explant, compared to 48% (28/59) in the HGD group. No neoplasia was found in 42% (12/29) of LGD and 24% (14/59) of HGD cases, meaning nearly one-third of patients transplanted for suspected bile duct dysplasia had no histological evidence of neoplasia in the explant. Five-year post-transplant survival according to the explant histology was 95% for no neoplasia, 89% for LGD, 85% for HGD, decreasing to 33% in those with CCA in the explant.
Conclusions
While favorable survival in confirmed dysplasia supports the role of preemptive LT, the absence of neoplasia in a substantial proportion of explants, particularly in suspected LGD, calls for a cautious, individualized approach. LT appears more clearly justified in accurately diagnosed HGD, given its strong association with early malignancy and the poor prognosis of advanced CCA.
Impact and implications
Individuals with primary sclerosing cholangitis (PSC) are at increased risk of developing bile duct cancer. In precancerous stages (bile duct dysplasia), liver transplantation (LT) may prevent progression to advanced, incurable cancer. In our evaluation of 512 patients with PSC who underwent LT, we found that the low diagnostic accuracy and unpredictable detection of mild dysplasia support a cautious, individualized approach to LT in precancerous stages of PSC, while more advanced dysplasia remains a valid indication for LT.
{"title":"A retrospective evaluation of preemptive liver transplantation for bile duct dysplasia in primary sclerosing cholangitis: Balancing risks and benefits","authors":"Sigurd Breder , Christina Villard , Emma Eide , Benny Wang , Lise Katrine Engesæter , Henrik Mikael Reims , Johannes Roksund Hov , Espen Melum , Lars Aabakken , Pål Dag Line , Jon Lømo , Krzyztof Grzyb , Kristine Wiencke , Annika Bergquist , Trine Folseraas","doi":"10.1016/j.jhepr.2025.101598","DOIUrl":"10.1016/j.jhepr.2025.101598","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver transplantation (LT) to prevent cholangiocarcinoma (CCA) in individuals with primary sclerosing cholangitis (PSC) and bile duct dysplasia was introduced in Norway and Sweden in the early 2000s. We aimed to evaluate this practice to potentially improve future selection of candidates for LT.</div></div><div><h3>Methods</h3><div>We conducted a retrospective study of 512 adults with PSC who underwent first-time LT between 2000–2021 at Oslo and Karolinska University Hospitals. Pre-LT findings in bile duct brush cytology and/or biopsy of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) were compared with histological findings in the explanted livers and survival rates were assessed.</div></div><div><h3>Results</h3><div>Bile duct dysplasia, low-grade (LGD) or high-grade (HGD), was the primary LT indication in 17% (88/512). Among individuals transplanted for LGD, only 10% (3/29) had HGD or CCA in the explant, compared to 48% (28/59) in the HGD group. No neoplasia was found in 42% (12/29) of LGD and 24% (14/59) of HGD cases, meaning nearly one-third of patients transplanted for suspected bile duct dysplasia had no histological evidence of neoplasia in the explant. Five-year post-transplant survival according to the explant histology was 95% for no neoplasia, 89% for LGD, 85% for HGD, decreasing to 33% in those with CCA in the explant.</div></div><div><h3>Conclusions</h3><div>While favorable survival in confirmed dysplasia supports the role of preemptive LT, the absence of neoplasia in a substantial proportion of explants, particularly in suspected LGD, calls for a cautious, individualized approach. LT appears more clearly justified in accurately diagnosed HGD, given its strong association with early malignancy and the poor prognosis of advanced CCA.</div></div><div><h3>Impact and implications</h3><div>Individuals with primary sclerosing cholangitis (PSC) are at increased risk of developing bile duct cancer. In precancerous stages (bile duct dysplasia), liver transplantation (LT) may prevent progression to advanced, incurable cancer. In our evaluation of 512 patients with PSC who underwent LT, we found that the low diagnostic accuracy and unpredictable detection of mild dysplasia support a cautious, individualized approach to LT in precancerous stages of PSC, while more advanced dysplasia remains a valid indication for LT.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101598"},"PeriodicalIF":7.5,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518449","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 : 2025-09-18DOI: 10.1016/j.jhepr.2025.101596
Muhammad Atif Zahoor , Nahla FadlElMawla , Adrian Kuipery , Joshua B. Feld , Avisha Chowdhury , Alexander I. Mosa , Adam J. Gehring , Jordan J. Feld
Background & Aims
Chronic HBV infection is a leading cause of liver disease and cancer. Current therapies fail to eliminate covalently closed circular DNA (cccDNA), underscoring the need for novel strategies. We aimed to develop a quantitative cell-based reporter system that detects HBx expression during HBV infection and is suitable for screening compounds with anti-HBV activity.
Methods
We generated an HBx-responsive cell line stably expressing nano-luciferase (nLuc) under the control of a viral cAMP-response element (vCRE) derived from the human T-cell leukemia virus-1 core promoter. The system was used to evaluate various drug inhibitors in HBV-infected cells.
Results
The vCRE-nLuc system was confirmed to be responsive to HBx using pHBV1.3-wild-type, pHBV1.3-null-X and pMyc-HBx constructs (p <0.0001). HBV infection with both culture-derived and patient-derived clinical isolates (genotypes A-E) significantly increased luciferase activity (p <0.0001). Treatment with HBx inhibitors (siRNA, specific HBx inhibitors), as well as IFNα reduced luciferase production (p <0.0001). In contrast, antivirals that do not interfere with protein production (tenofovir), or viral entry (bulevirtide) showed no effect (p <0.05), underscoring the specificity of the system for identifying compounds that inhibit protein production and/or HBx function. Finally, HepG2.2.15 cells carrying HBV and transduced with vCRE-nLuc confirmed the system’s suitability for monitoring HBV infection.
Conclusions
We established a vCRE-nLuc-driven HBx-responsive cell line for quantitative monitoring of HBV infection and evaluation of antiviral drugs. This system holds potential for identifying new anti-HBV agents and advancing our understanding of HBV replication.
Impact and implications
The HBx-responsive vCRE-nLuc reporter system provides a sensitive and scalable platform to monitor HBV infection and evaluate antiviral compounds targeting HBx function. Its ability to detect HBx activity from both laboratory and clinical HBV isolates underscore its translational relevance. By enabling selective screening of HBx-targeting agents, this system may advance efforts to silence covalently closed circular DNA and accelerate the development of curative therapies for chronic hepatitis B.
{"title":"Development of a CRE/CREB-driven HBx responsive HBV cell culture reporter system for antiviral drug evaluation","authors":"Muhammad Atif Zahoor , Nahla FadlElMawla , Adrian Kuipery , Joshua B. Feld , Avisha Chowdhury , Alexander I. Mosa , Adam J. Gehring , Jordan J. Feld","doi":"10.1016/j.jhepr.2025.101596","DOIUrl":"10.1016/j.jhepr.2025.101596","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Chronic HBV infection is a leading cause of liver disease and cancer. Current therapies fail to eliminate covalently closed circular DNA (cccDNA), underscoring the need for novel strategies. We aimed to develop a quantitative cell-based reporter system that detects HBx expression during HBV infection and is suitable for screening compounds with anti-HBV activity.</div></div><div><h3>Methods</h3><div>We generated an HBx-responsive cell line stably expressing nano-luciferase (nLuc) under the control of a viral cAMP-response element (vCRE) derived from the human T-cell leukemia virus-1 core promoter. The system was used to evaluate various drug inhibitors in HBV-infected cells.</div></div><div><h3>Results</h3><div>The vCRE-nLuc system was confirmed to be responsive to HBx using pHBV1.3-wild-type, pHBV1.3-null-X and pMyc-HBx constructs (<em>p <</em>0.0001). HBV infection with both culture-derived and patient-derived clinical isolates (genotypes A-E) significantly increased luciferase activity (<em>p <</em>0.0001). Treatment with HBx inhibitors (siRNA, specific HBx inhibitors), as well as IFNα reduced luciferase production (<em>p <</em>0.0001). In contrast, antivirals that do not interfere with protein production (tenofovir), or viral entry (bulevirtide) showed no effect (<em>p <</em>0.05), underscoring the specificity of the system for identifying compounds that inhibit protein production and/or HBx function. Finally, HepG2.2.15 cells carrying HBV and transduced with vCRE-nLuc confirmed the system’s suitability for monitoring HBV infection.</div></div><div><h3>Conclusions</h3><div>We established a vCRE-nLuc-driven HBx-responsive cell line for quantitative monitoring of HBV infection and evaluation of antiviral drugs. This system holds potential for identifying new anti-HBV agents and advancing our understanding of HBV replication.</div></div><div><h3>Impact and implications</h3><div>The HBx-responsive vCRE-nLuc reporter system provides a sensitive and scalable platform to monitor HBV infection and evaluate antiviral compounds targeting HBx function. Its ability to detect HBx activity from both laboratory and clinical HBV isolates underscore its translational relevance. By enabling selective screening of HBx-targeting agents, this system may advance efforts to silence covalently closed circular DNA and accelerate the development of curative therapies for chronic hepatitis B.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101596"},"PeriodicalIF":7.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517866","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 : 2025-09-18DOI: 10.1016/j.jhepr.2025.101597
Adrià Juanola , Gabriel Mezzano , Elisa Pose , Maria J. Moreta , Simone Incicco , Roberta Gagliardi , Stine Johansen , Nikolaj Torp , Mads Israelsen , Natalia Jiménez-Esquivel , Joaquin Castillo-Iturra , Jordi Ribera , Jordi Gratacós-Ginès , Anna Soria , Andrés Cárdenas , Martina Pérez-Guasch , Marta Cervera , Ruth Nadal , Queralt Herms , Marta Tonon , Pere Ginès
Background & Aims
Impaired phagocytic capacity due to activation of the PD-1/PD-L1 pathway has been implicated in the development of bacterial infections in patients with cirrhosis. Soluble PD-L1 (sPD-L1) is easily measurable in plasma and has been proposed as a biomarker of sepsis. In the current study, we aim to evaluate the role of sPD-L1 as a biomarker of bacterial infection development in patients with cirrhosis.
Methods
Plasma samples from 995 patients with chronic liver disease grouped in three cohorts were analyzed: an initial cohort of 268 hospitalized patients with acute decompensated cirrhosis, 327 out-patients with non-acute decompensated cirrhosis and finally 400 patients with high-risk alcohol consumption, including all stages of liver fibrosis, from mild/no fibrosis to cirrhosis (F0–F4). The main outcomes of the study were development of bacterial infection and mortality.
Results
Patients who developed bacterial infections had higher median levels of sPD-L1 than those who did not (160 [IQR 116-221] vs. 136 [IQR 97-193] pg/ml, respectively, p value <0.001; hazard ratio 1.034, 95% CI 1.014-1.055). Levels of sPD-L1 were associated with bacterial infection development after adjustment for confounding factors. During follow-up, patients who died had higher median sPD-L1 levels than survivors, after adjustment for MELD Na (180 [IQR 143-267] vs. 134 [IQR 97-187] pg/ml, respectively; p value <0.001; HR 1.066, 95% CI 1.043-1.089). These findings were observed in all cohorts.
Conclusions
Plasma levels of sPD-L1 are associated with the risk of bacterial infection development irrespective of the stage of chronic liver disease. Furthermore, higher sPD-L1 levels are linked to increased mortality. Measurement of sPD-L1 levels may help identify patients at high risk of developing bacterial infections and guide the implementation of new preventive strategies.
Impact and implications
This study explores the role of soluble PD-L1 as a biomarker of immune dysfunction and its association with clinical outcomes in patients with chronic liver disease. Our findings demonstrate that soluble PD-L1 levels increase with the progression of liver disease and they are independently associated with an increased risk of bacterial infection development and mortality. These results could help physicians identify high-risk individuals earlier and implement preventive strategies.
{"title":"PD-L1 and the risk of bacterial infection in patients with chronic liver diseases: An international multicohort study","authors":"Adrià Juanola , Gabriel Mezzano , Elisa Pose , Maria J. Moreta , Simone Incicco , Roberta Gagliardi , Stine Johansen , Nikolaj Torp , Mads Israelsen , Natalia Jiménez-Esquivel , Joaquin Castillo-Iturra , Jordi Ribera , Jordi Gratacós-Ginès , Anna Soria , Andrés Cárdenas , Martina Pérez-Guasch , Marta Cervera , Ruth Nadal , Queralt Herms , Marta Tonon , Pere Ginès","doi":"10.1016/j.jhepr.2025.101597","DOIUrl":"10.1016/j.jhepr.2025.101597","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Impaired phagocytic capacity due to activation of the PD-1/PD-L1 pathway has been implicated in the development of bacterial infections in patients with cirrhosis. Soluble PD-L1 (sPD-L1) is easily measurable in plasma and has been proposed as a biomarker of sepsis. In the current study, we aim to evaluate the role of sPD-L1 as a biomarker of bacterial infection development in patients with cirrhosis.</div></div><div><h3>Methods</h3><div>Plasma samples from 995 patients with chronic liver disease grouped in three cohorts were analyzed: an initial cohort of 268 hospitalized patients with acute decompensated cirrhosis, 327 out-patients with non-acute decompensated cirrhosis and finally 400 patients with high-risk alcohol consumption, including all stages of liver fibrosis, from mild/no fibrosis to cirrhosis (F0–F4). The main outcomes of the study were development of bacterial infection and mortality.</div></div><div><h3>Results</h3><div>Patients who developed bacterial infections had higher median levels of sPD-L1 than those who did not (160 [IQR 116-221] <em>vs</em>. 136 [IQR 97-193] pg/ml, respectively, <em>p</em> value <0.001; hazard ratio 1.034, 95% CI 1.014-1.055). Levels of sPD-L1 were associated with bacterial infection development after adjustment for confounding factors. During follow-up, patients who died had higher median sPD-L1 levels than survivors, after adjustment for MELD Na (180 [IQR 143-267] <em>vs.</em> 134 [IQR 97-187] pg/ml, respectively; <em>p</em> value <0.001; HR 1.066, 95% CI 1.043-1.089). These findings were observed in all cohorts.</div></div><div><h3>Conclusions</h3><div>Plasma levels of sPD-L1 are associated with the risk of bacterial infection development irrespective of the stage of chronic liver disease. Furthermore, higher sPD-L1 levels are linked to increased mortality. Measurement of sPD-L1 levels may help identify patients at high risk of developing bacterial infections and guide the implementation of new preventive strategies.</div></div><div><h3>Impact and implications</h3><div>This study explores the role of soluble PD-L1 as a biomarker of immune dysfunction and its association with clinical outcomes in patients with chronic liver disease. Our findings demonstrate that soluble PD-L1 levels increase with the progression of liver disease and they are independently associated with an increased risk of bacterial infection development and mortality. These results could help physicians identify high-risk individuals earlier and implement preventive strategies.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101597"},"PeriodicalIF":7.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518454","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 : 2025-09-18DOI: 10.1016/j.jhepr.2025.101594
José Ursic Bedoya , Charlotte De Choudens , Margaux Delhomme , Astrid Herrero , Stéphanie Faure , Lucy Meunier , Magdalena Meszaros , Georges-Philippe Pageaux , Claire Duflos
Background & Aims
Several studies have shown that non-medical factors can determine access to liver transplantation (LT). Most of these studies are from North America, where the healthcare system has specific features that may not be generalisable to Europe. We investigated the factors associated with access to LT in patients admitted for a first episode of decompensated cirrhosis in France and to determine potential treatment gaps according to disease aetiology.
Methods
We conducted a retrospective cohort study using the French national health data system to identify patients hospitalised for a first decompensation of cirrhosis between 2015 and 2022, followed until December 2023. We built a frailty model to search for factors associated with access to LT and to quantify inter-centre variability. Then, we compared survival rates and incidence of liver-related death according to disease aetiology, including competing risk analyses.
Results
We identified 65,771 patients (73.5% men, 82.3% alcohol-related liver disease [ALD]), with a mean follow-up time of 36 months. Of these patients, 3,596 (5.5%) were transplanted and 35,660 (54.2%) died. Patients with ALD were less likely to be transplanted (hazard ratio [HR] 0.75, 95% CI 0.69–0.81, p <0.0001), as were women (HR 0.75, 95% CI 0.69–0.81, p <0.0001), patients with solidarity-based health insurance (HR 0.82, 95% CI 0.74–0.90, p <0.0001) and those from socially deprived backgrounds (HR 0.97, 95% CI 0.94–0.99, p = 0.01). Restricted LT access for patients with ALD was associated with lower survival rates and increased liver-related mortality compared with non-ALD patients.
Conclusions
Our study highlights several factors contributing to unequal access to LT in France. Reduced access for patients with ALD suggests the presence of structural stigma.
Impact and implications
This study provides the first national-level evidence from a European country showing that patients with alcohol-related cirrhosis, particularly women and those from socioeconomically disadvantaged backgrounds, experience lower access to liver transplantation and higher liver-related mortality. These findings could be important for clinicians, researchers, and health policymakers seeking to improve equity in transplant access within universal healthcare systems. While our study does not capture all clinical or psychosocial determinants of transplant eligibility, it highlights systemic disparities that could be mitigated through national referral protocols, standardised patient evaluations, and targeted support for vulnerable populations. Future work should integrate clinical data and patient-reported outcomes to further refine these observations and guide practice change.
背景和目的几项研究表明，非医学因素可以决定肝移植（LT）的可及性。这些研究大多来自北美，那里的医疗保健系统有特定的特点，可能不适用于欧洲。我们调查了与法国首次失代偿性肝硬化患者接受肝移植相关的因素，并根据疾病病因确定潜在的治疗缺口。方法：我们使用法国国家健康数据系统进行了一项回顾性队列研究，以确定2015年至2022年期间因肝硬化首次失代偿住院的患者，随访至2023年12月。我们建立了一个脆弱性模型来寻找与获得LT相关的因素，并量化中心间的变异性。然后，我们根据疾病病因，包括竞争风险分析，比较了肝脏相关死亡的生存率和发生率。结果65,771例患者（73.5%为男性，82.3%为酒精相关性肝病[ALD]），平均随访时间36个月。其中3596例（5.5%）移植，35660例（54.2%）死亡。ALD患者移植的可能性较低（风险比[HR] 0.75, 95% CI 0.69-0.81, p <0.0001），女性（风险比[HR] 0.75, 95% CI 0.69-0.81, p <0.0001），有团结医疗保险的患者（风险比[HR] 0.82, 95% CI 0.74-0.90, p <0.0001）和社会贫困背景的患者（风险比[HR] 0.97, 95% CI 0.94-0.99, p = 0.01）。与非ALD患者相比，ALD患者的肝移植受限与较低的生存率和较高的肝脏相关死亡率相关。结论我们的研究强调了导致法国LT获取不平等的几个因素。ALD患者获取途径的减少表明存在结构性耻辱感。影响和意义本研究首次提供了来自欧洲国家的国家级证据，表明酒精相关性肝硬化患者，特别是女性和社会经济背景不利的患者，接受肝移植的机会较低，肝脏相关死亡率较高。这些发现可能对临床医生、研究人员和卫生政策制定者寻求在全民医疗保健系统中提高移植可及性的公平性具有重要意义。虽然我们的研究没有捕捉到移植资格的所有临床或社会心理决定因素，但它强调了可以通过国家转诊协议、标准化的患者评估和对弱势群体的有针对性的支持来缓解的系统性差异。未来的工作应整合临床数据和患者报告的结果，以进一步完善这些观察结果并指导实践变革。
{"title":"Disparities in transplant access and outcomes after first cirrhosis decompensation in alcohol-related liver disease","authors":"José Ursic Bedoya , Charlotte De Choudens , Margaux Delhomme , Astrid Herrero , Stéphanie Faure , Lucy Meunier , Magdalena Meszaros , Georges-Philippe Pageaux , Claire Duflos","doi":"10.1016/j.jhepr.2025.101594","DOIUrl":"10.1016/j.jhepr.2025.101594","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Several studies have shown that non-medical factors can determine access to liver transplantation (LT). Most of these studies are from North America, where the healthcare system has specific features that may not be generalisable to Europe. We investigated the factors associated with access to LT in patients admitted for a first episode of decompensated cirrhosis in France and to determine potential treatment gaps according to disease aetiology.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study using the French national health data system to identify patients hospitalised for a first decompensation of cirrhosis between 2015 and 2022, followed until December 2023. We built a frailty model to search for factors associated with access to LT and to quantify inter-centre variability. Then, we compared survival rates and incidence of liver-related death according to disease aetiology, including competing risk analyses.</div></div><div><h3>Results</h3><div>We identified 65,771 patients (73.5% men, 82.3% alcohol-related liver disease [ALD]), with a mean follow-up time of 36 months. Of these patients, 3,596 (5.5%) were transplanted and 35,660 (54.2%) died. Patients with ALD were less likely to be transplanted (hazard ratio [HR] 0.75, 95% CI 0.69–0.81, <em>p</em> <0.0001), as were women (HR 0.75, 95% CI 0.69–0.81, <em>p</em> <0.0001), patients with solidarity-based health insurance (HR 0.82, 95% CI 0.74–0.90, <em>p</em> <0.0001) and those from socially deprived backgrounds (HR 0.97, 95% CI 0.94–0.99, <em>p</em> = 0.01). Restricted LT access for patients with ALD was associated with lower survival rates and increased liver-related mortality compared with non-ALD patients.</div></div><div><h3>Conclusions</h3><div>Our study highlights several factors contributing to unequal access to LT in France. Reduced access for patients with ALD suggests the presence of structural stigma.</div></div><div><h3>Impact and implications</h3><div>This study provides the first national-level evidence from a European country showing that patients with alcohol-related cirrhosis, particularly women and those from socioeconomically disadvantaged backgrounds, experience lower access to liver transplantation and higher liver-related mortality. These findings could be important for clinicians, researchers, and health policymakers seeking to improve equity in transplant access within universal healthcare systems. While our study does not capture all clinical or psychosocial determinants of transplant eligibility, it highlights systemic disparities that could be mitigated through national referral protocols, standardised patient evaluations, and targeted support for vulnerable populations. Future work should integrate clinical data and patient-reported outcomes to further refine these observations and guide practice change.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101594"},"PeriodicalIF":7.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145464735","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 : 2025-09-11DOI: 10.1016/j.jhepr.2025.101588
Kunjin Wu , Jing Li , Yunong Fu , Kaibo Yang , Ting Lin , Yaohui Wang , Ming Wang , Yunxiang Long , Fengping Zhang , Bo Cheng , Yuan Li , Cong Wang , Feng Xu , Chang Liu , Kai Qu
<div><h3>Background & Aims</h3><div>Hepatocellular carcinoma (HCC) displays heterogeneous responses to lenvatinib, with tumor microenvironment (TME) stiffness emerging as a key resistance modulator. This study investigates how tumor peripheral stiffness governs lenvatinib efficacy via mitochondrial fission/mitophagy and evaluates matrix-targeting combination therapies.</div></div><div><h3>Methods</h3><div>Clinical HCC tissues underwent stiffness measurement (atomic force microscopy [AFM]/rheometry) and survival correlation analyses. <em>In vitro</em>, cells grown on soft <em>vs.</em> stiff hydrogels (5 <em>vs.</em> 15 kPa) were assessed for their lenvatinib response, mitophagy, and mitochondrial fission 1 (FIS1)–trimethylation of histone H3 lysine 27 (H3K27me3) regulation. Subcutaneous xenografts received collagenase-lenvatinib combination therapy.</div></div><div><h3>Results</h3><div>Elevated tumor peripheral stiffness, quantified by AFM and rotational rheometry, was significantly associated with HCC recurrence. Patients with stiff peripheries exhibited reduced recurrence-free survival (<em>p</em> <0.05), correlating with upregulated mitophagy markers (Parkin and FIS1) and diminished H3K27me3 in high-stiffness human HCC tissues (<em>p</em> <0.0001). <em>In vitro</em>, HCC cells on stiff matrices (15 kPa) showed attenuated lenvatinib-induced apoptosis (TUNEL: <em>p</em> = 0.0003 <em>vs.</em> soft 5 kPa) and preserved mitochondrial membrane potential (JC-1: <em>p</em> = 0.0004), concomitant with fragmented mitochondria driven by FIS1 upregulation via H3K27me3 depletion at its promoter (chromatin immunoprecipitation: <em>p</em> <0.0001). FIS1 knockdown reversed mitochondrial fragmentation (<em>p</em> <0.001) and resensitized cells to lenvatinib. Stiffness amplified cytoprotective mitophagy under lenvatinib stress, evidenced by enhanced LC3/TOM20 colocalization (<em>p</em> = 0.0008) and mitochondrial Parkin accumulation. <em>In vivo</em>, collagenase-mediated matrix softening synergized with lenvatinib, suppressing tumor growth (volume: <em>p</em> <0.001; weight: <em>p</em> <0.001) while reducing FIS1/Parkin expression and augmenting apoptosis.</div></div><div><h3>Conclusions</h3><div>Tumor peripheral stiffness drives lenvatinib resistance in HCC via H3K27me3-mediated FIS1 upregulation, triggering mitochondrial fission and cytoprotective mitophagy to evade drug-induced apoptosis. Targeting matrix stiffness (via collagenase-mediated softening) synergizes with lenvatinib to overcome microenvironment-driven resistance, providing a novel mechanoadjuvant strategy for HCC therapy.</div></div><div><h3>Impact and implications</h3><div>This study shows that tumor peripheral matrix stiffness reduces lenvatinib sensitivity in HCC by enhancing FIS1-dependent mitophagy, explaining therapeutic response heterogeneity. These findings are clinically relevant, highlighting tumor stiffness as a potential biomarker for lenvatinib resistance and mi
{"title":"Tumor peripheral stiffness modulates lenvatinib resistance in HCC preclinical models by regulating FIS1-dependent mitophagy","authors":"Kunjin Wu , Jing Li , Yunong Fu , Kaibo Yang , Ting Lin , Yaohui Wang , Ming Wang , Yunxiang Long , Fengping Zhang , Bo Cheng , Yuan Li , Cong Wang , Feng Xu , Chang Liu , Kai Qu","doi":"10.1016/j.jhepr.2025.101588","DOIUrl":"10.1016/j.jhepr.2025.101588","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Hepatocellular carcinoma (HCC) displays heterogeneous responses to lenvatinib, with tumor microenvironment (TME) stiffness emerging as a key resistance modulator. This study investigates how tumor peripheral stiffness governs lenvatinib efficacy via mitochondrial fission/mitophagy and evaluates matrix-targeting combination therapies.</div></div><div><h3>Methods</h3><div>Clinical HCC tissues underwent stiffness measurement (atomic force microscopy [AFM]/rheometry) and survival correlation analyses. <em>In vitro</em>, cells grown on soft <em>vs.</em> stiff hydrogels (5 <em>vs.</em> 15 kPa) were assessed for their lenvatinib response, mitophagy, and mitochondrial fission 1 (FIS1)–trimethylation of histone H3 lysine 27 (H3K27me3) regulation. Subcutaneous xenografts received collagenase-lenvatinib combination therapy.</div></div><div><h3>Results</h3><div>Elevated tumor peripheral stiffness, quantified by AFM and rotational rheometry, was significantly associated with HCC recurrence. Patients with stiff peripheries exhibited reduced recurrence-free survival (<em>p</em> <0.05), correlating with upregulated mitophagy markers (Parkin and FIS1) and diminished H3K27me3 in high-stiffness human HCC tissues (<em>p</em> <0.0001). <em>In vitro</em>, HCC cells on stiff matrices (15 kPa) showed attenuated lenvatinib-induced apoptosis (TUNEL: <em>p</em> = 0.0003 <em>vs.</em> soft 5 kPa) and preserved mitochondrial membrane potential (JC-1: <em>p</em> = 0.0004), concomitant with fragmented mitochondria driven by FIS1 upregulation via H3K27me3 depletion at its promoter (chromatin immunoprecipitation: <em>p</em> <0.0001). FIS1 knockdown reversed mitochondrial fragmentation (<em>p</em> <0.001) and resensitized cells to lenvatinib. Stiffness amplified cytoprotective mitophagy under lenvatinib stress, evidenced by enhanced LC3/TOM20 colocalization (<em>p</em> = 0.0008) and mitochondrial Parkin accumulation. <em>In vivo</em>, collagenase-mediated matrix softening synergized with lenvatinib, suppressing tumor growth (volume: <em>p</em> <0.001; weight: <em>p</em> <0.001) while reducing FIS1/Parkin expression and augmenting apoptosis.</div></div><div><h3>Conclusions</h3><div>Tumor peripheral stiffness drives lenvatinib resistance in HCC via H3K27me3-mediated FIS1 upregulation, triggering mitochondrial fission and cytoprotective mitophagy to evade drug-induced apoptosis. Targeting matrix stiffness (via collagenase-mediated softening) synergizes with lenvatinib to overcome microenvironment-driven resistance, providing a novel mechanoadjuvant strategy for HCC therapy.</div></div><div><h3>Impact and implications</h3><div>This study shows that tumor peripheral matrix stiffness reduces lenvatinib sensitivity in HCC by enhancing FIS1-dependent mitophagy, explaining therapeutic response heterogeneity. These findings are clinically relevant, highlighting tumor stiffness as a potential biomarker for lenvatinib resistance and mi","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101588"},"PeriodicalIF":7.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568401","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 : 2025-09-11DOI: 10.1016/j.jhepr.2025.101592
Tobias Paul Seraphin , Agavni Mesropian , Laura Žigutytė , James Brooks , Ezequiel Mauro , Albert Gris-Oliver , Roser Pinyol , Carla Montironi , Ugne Balaseviciute , Marta Piqué-Gili , Júlia Huguet-Pradell , Marko van Treeck , Michael Kallenbach , Anne Theres Schneider , Christoph Roderburg , Jakob Nikolas Kather , Tom Luedde , Josep M. Llovet
<div><h3>Background & Aims</h3><div>Advances in digital pathology and artificial intelligence (AI) are driving progress toward personalized clinical management. In hepatocellular carcinoma (HCC), AI-based models using digitized H&E slides can be a robust tool to predict outcome-related molecular profiles and presence of microvascular invasion (mVI), with potential clinical utility.</div></div><div><h3>Methods</h3><div>A transformer-based deep-learning (DL) model was deployed using digitized H&E slides from 431 resected HCC cases (training cohort). Five-fold cross-validation was applied, and the model was tested on two external cohorts: TCGA-LIHC (n = 363) and advanced-stage HCC cohort (n = 64).</div></div><div><h3>Results</h3><div>The DL model effectively predicted outcome-related molecular profiles, distinguishing poor-prognosis (<em>S1</em>/<em>S2,</em> proliferation) from good-prognosis (<em>S3,</em> non-proliferation) subclasses. In internal cross-validation, mean areas under the curves (AUCs) were 0.75 for proliferation and 0.79 for non-proliferation subclasses<em>.</em> This performance was reproduced in the TCGA test set, with AUCs ranging from 0.72–0.80, and in the advanced-stage HCC cohort, with AUCs ranging from 0.76–0.81. In these test sets, the AI-predicted non-proliferation subclass was associated with a longer median OS compared with the proliferation subclass (5.8 <em>vs.</em> 3.5 years in TCGA; <em>p</em> = 0.02). For mVI prediction, the DL model achieved a mean AUC of 0.70 in the internal cross-validation and 0.62 in the TCGA. AI-predicted mVI was associated with shorter OS (4.9 <em>vs.</em> 7.6 years for non-mVI; <em>p =</em> 0.003) and an immunosuppressive microenvironment (<em>p =</em> 0.002).</div></div><div><h3>Conclusions</h3><div>Our H&E-based AI model enables accurate prediction of outcome-related molecular subtypes of poor prognosis and presence of mVI, offering a scalable and accessible tool to extract clinically relevant features from routine histology.</div></div><div><h3>Impact and implications</h3><div>Outcome-related molecular profiles and the presence of microvascular invasion (mVI) are critical determinants of prognosis and treatment decisions in hepatocellular carcinoma (HCC). This study presents an artificial intelligence (AI)-based method that analyzes routine H&E-stained slides and accurately predicts: (a) biologically relevant HCC molecular subtypes associated with patient outcomes, and (b) the presence of mVI, a well-established predictor of poor outcomes and risk of recurrence, that currently requires meticulous pathological assessment of multiple H&E slides. These AI tools can offer a scalable method to support personalized treatment decisions, such as transplant eligibility, trial enrollment, or neo/adjuvant therapy planning, and may improve clinical management of HCC. Our findings lay the groundwork for incorporating AI-assisted pathology into future prospective studies aimed at
{"title":"Artificial intelligence predicts outcome-related molecular profiles and vascular invasion in hepatocellular carcinoma","authors":"Tobias Paul Seraphin , Agavni Mesropian , Laura Žigutytė , James Brooks , Ezequiel Mauro , Albert Gris-Oliver , Roser Pinyol , Carla Montironi , Ugne Balaseviciute , Marta Piqué-Gili , Júlia Huguet-Pradell , Marko van Treeck , Michael Kallenbach , Anne Theres Schneider , Christoph Roderburg , Jakob Nikolas Kather , Tom Luedde , Josep M. Llovet","doi":"10.1016/j.jhepr.2025.101592","DOIUrl":"10.1016/j.jhepr.2025.101592","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Advances in digital pathology and artificial intelligence (AI) are driving progress toward personalized clinical management. In hepatocellular carcinoma (HCC), AI-based models using digitized H&E slides can be a robust tool to predict outcome-related molecular profiles and presence of microvascular invasion (mVI), with potential clinical utility.</div></div><div><h3>Methods</h3><div>A transformer-based deep-learning (DL) model was deployed using digitized H&E slides from 431 resected HCC cases (training cohort). Five-fold cross-validation was applied, and the model was tested on two external cohorts: TCGA-LIHC (n = 363) and advanced-stage HCC cohort (n = 64).</div></div><div><h3>Results</h3><div>The DL model effectively predicted outcome-related molecular profiles, distinguishing poor-prognosis (<em>S1</em>/<em>S2,</em> proliferation) from good-prognosis (<em>S3,</em> non-proliferation) subclasses. In internal cross-validation, mean areas under the curves (AUCs) were 0.75 for proliferation and 0.79 for non-proliferation subclasses<em>.</em> This performance was reproduced in the TCGA test set, with AUCs ranging from 0.72–0.80, and in the advanced-stage HCC cohort, with AUCs ranging from 0.76–0.81. In these test sets, the AI-predicted non-proliferation subclass was associated with a longer median OS compared with the proliferation subclass (5.8 <em>vs.</em> 3.5 years in TCGA; <em>p</em> = 0.02). For mVI prediction, the DL model achieved a mean AUC of 0.70 in the internal cross-validation and 0.62 in the TCGA. AI-predicted mVI was associated with shorter OS (4.9 <em>vs.</em> 7.6 years for non-mVI; <em>p =</em> 0.003) and an immunosuppressive microenvironment (<em>p =</em> 0.002).</div></div><div><h3>Conclusions</h3><div>Our H&E-based AI model enables accurate prediction of outcome-related molecular subtypes of poor prognosis and presence of mVI, offering a scalable and accessible tool to extract clinically relevant features from routine histology.</div></div><div><h3>Impact and implications</h3><div>Outcome-related molecular profiles and the presence of microvascular invasion (mVI) are critical determinants of prognosis and treatment decisions in hepatocellular carcinoma (HCC). This study presents an artificial intelligence (AI)-based method that analyzes routine H&E-stained slides and accurately predicts: (a) biologically relevant HCC molecular subtypes associated with patient outcomes, and (b) the presence of mVI, a well-established predictor of poor outcomes and risk of recurrence, that currently requires meticulous pathological assessment of multiple H&E slides. These AI tools can offer a scalable method to support personalized treatment decisions, such as transplant eligibility, trial enrollment, or neo/adjuvant therapy planning, and may improve clinical management of HCC. Our findings lay the groundwork for incorporating AI-assisted pathology into future prospective studies aimed at ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101592"},"PeriodicalIF":7.5,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518452","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}
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