JHEP Reports最新文献

{"title":"Pre-emptive TIPS should be considered in high-risk patients with both acute variceal bleeding and severe alcohol-related hepatitis","authors":"Marika Rudler ,&nbsp;Virginia Hernandez Gea ,&nbsp;Hélène Larrue ,&nbsp;Charlotte Bouzbib ,&nbsp;Bogdan Procopet ,&nbsp;Anna Baiges ,&nbsp;Fanny Turon ,&nbsp;Candido Villanueva ,&nbsp;Agustin Albillos ,&nbsp;Edilmar Alvarado Tapias ,&nbsp;Lise Lott Gluud ,&nbsp;Michael Praktiknjo ,&nbsp;Joan Genesca ,&nbsp;Meritxell Ventura-Cots ,&nbsp;Ares Villagrasa ,&nbsp;Susanna Rodrigues ,&nbsp;Sarah Mouri ,&nbsp;Álvaro Giráldez-Gallego ,&nbsp;Helena Masnou Ridaura ,&nbsp;Wim Laleman ,&nbsp;Dominique Thabut","doi":"10.1016/j.jhepr.2025.101611","DOIUrl":"10.1016/j.jhepr.2025.101611","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Severe alcohol-related hepatitis (AH) and acute variceal bleeding (AVB) may occur simultaneously. The impact of a pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) in high-risk patients (patients with Child–Pugh (CP) B and active bleeding or CP C10–13 cirrhosis) with AVB and concomitant severe AH is unknown. The objective of the study was to compare the outcomes of severe AH in patients with high-risk AVB treated with pTIPS or endoscopic and drug treatment (Endo+drugs).</div></div><div><h3>Methods</h3><div>Patients were screened in four existing cohorts of patients with cirrhosis and AVB treated either with pTIPS or Endo+drugs. The inclusion criteria were AVB, high-risk patients, suspected severe AH (recent onset of jaundice, alcohol-related liver disease, absence of abstinence, model for end-stage liver disease score &gt;20 and aspartate aminotransferase &lt;500 UI/L). The primary endpoint was 42-day mortality, considering liver transplantation as a competing event. Secondary endpoints were rebleeding and further development of ascites or hepatic encephalopathy at 6 months.</div></div><div><h3>Results</h3><div>A total of 142 patients with AVB were included (pTIPS: n = 47, Endo+drugs: n = 95). Baseline characteristics (age 53, male sex 84%, model for end-stage liver disease score 23.4) were similar between the two groups. Overall, 56% had histologically proven AH. The 42-day mortality was 16% in the pTIPS group <em>vs.</em> 30% in the Endo+drugs group (<em>p</em> = 0.2). The cumulative incidence of rebleeding and ascites was significantly lower in the pTIPS group (2.8% <em>vs.</em> 24%, <em>p</em> = 0.026, and 6% <em>vs.</em> 52%, <em>p</em> &lt;0.001, respectively), whereas hepatic encephalopathy occurrence was similar in the two groups (<em>p</em> = 0.2). Corticosteroid therapy was given in 55% and 46% of patients in the pTIPS and Endo+drugs groups, respectively (<em>p</em> = 0.3).</div></div><div><h3>Conclusions</h3><div>In severe AH, pTIPS is associated with better outcomes than Endo+drugs, and should not be contraindicated.</div></div><div><h3>Impact and implications</h3><div>Severe alcohol-related hepatitis and acute variceal bleeding may occur concomitantly, yet the role of pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) placement in this setting remains unclear. In this study, compared to standard of care, pTIPS treatment was associated with lower mortality, although this difference did not reach statistical significance, as well as a significantly reduced risk of rebleeding and recurrent ascites. These findings suggest that severe alcohol-related hepatitis should not be viewed as a contraindication to pTIPS placement when otherwise indicated, such as in patients with Child–Pugh B cirrhosis with a score greater than 7 and active bleeding, or Child–Pugh C10–13 disease.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101611"},"PeriodicalIF":7.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569492","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":"Macrophage MRC2 deficiency mitigates HFD-induced MASLD by downregulating CD147-regulated TNF-α production","authors":"Hui-Ru Kuo ,&nbsp;Kwei-Yan Liu ,&nbsp;Hsin-Ying Clair Chiou ,&nbsp;Yu-Fen Chung ,&nbsp;Li-Ting Wang ,&nbsp;Chih-Wen Wang ,&nbsp;Shih-Hsien Hsu ,&nbsp;Shau-Ku Huang ,&nbsp;Ming-Hong Lin","doi":"10.1016/j.jhepr.2025.101601","DOIUrl":"10.1016/j.jhepr.2025.101601","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain incompletely understood, and macrophage-associated chronic inflammation has been suggested to play a role. We investigated the potential contribution of mannose receptor type C 2 (MRC2), a transmembrane glycoprotein, to MASLD development.</div></div><div><h3>Methods</h3><div>Wild-type (WT) and <em>Mrc</em><em>2</em>-deficient mice were fed a high-fat diet (HFD) for 8 weeks. Mouse primary hepatocytes (MPHs) and bone marrow–derived macrophages (BMDMs) were stimulated with or without palmitic acid (PA) to assess the role of MRC2 in MASLD development.</div></div><div><h3>Results</h3><div>MRC2 levels were significantly elevated in patients with MASLD (n = 216, <em>p &lt;</em>0.0001) and in the livers of HFD-fed WT mice (n = 6–8, <em>p &lt;</em>0.01), correlating with disease severity. <em>Mrc</em><em>2</em>-null mice exhibited reduced HFD-induced weight gain and steatosis compared with WT mice (n = 6–8). MRC2 was predominantly expressed in hepatic macrophages, and conditioned medium from WT BMDMs enhanced PA-induced steatosis in MPHs (n = 6, <em>p &lt;</em>0.0001). This effect was absent when conditioned medium from <em>Mrc</em><em>2</em>-deficient BMDMs was used or when TNF-α–neutralizing antibodies or TNF receptor antagonists were added. Macrophage-specific <em>Mrc2</em> deficiency also reduced MASLD severity in HFD-fed mice (n = 6). Mechanistically, disruption of the MRC2–CD147 complex impaired CD147-mediated NF-κB signaling and reduced TNF-α release from BMDMs, thereby decreasing steatosis in co-cultured MPHs.</div></div><div><h3>Conclusions</h3><div>Macrophage MRC2 promotes HFD-induced hepatic steatosis via the MRC2–CD147 complex, revealing a novel mechanism contributing to MASLD progression.</div></div><div><h3>Impact and implications</h3><div>This study identifies the critical role of MRC2 in the development of high-fat diet-induced metabolic dysfunction-associated steatotic liver disease, providing a mechanistic understanding of its involvement in macrophage-mediated inflammation. <em>M</em><em>rc</em><em>2</em> deficiency alleviates hepatic inflammation and lipid accumulation by downregulating CD147-regulated TNF-α production in macrophages. The findings are particularly significant for researchers and clinicians focused on liver diseases, as they reveal a novel target – the macrophage MRC2-CD147 complex – for potential therapeutic intervention.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101601"},"PeriodicalIF":7.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High systemic inflammation response index and increased cardiovascular risk and mortality in MASLD: A prospective cohort study","authors":"Haixiang Zheng ,&nbsp;Kuangyi Wu ,&nbsp;Hong Zheng ,&nbsp;Guanlin Chen ,&nbsp;Yulong Lan ,&nbsp;Shuohua Chen ,&nbsp;Gavino Casu ,&nbsp;Leonardo Antonio Sechi ,&nbsp;Shouling Wu ,&nbsp;Gianpaolo Vidili ,&nbsp;Youren Chen","doi":"10.1016/j.jhepr.2025.101602","DOIUrl":"10.1016/j.jhepr.2025.101602","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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 &lt;em&gt;vs.&lt;/em&gt; 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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;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 &lt;em&gt;vs.&lt;/em&gt; Q1 1.21; 95% CI 1.10–1.31; &lt;em&gt;p &lt;&lt;/em&gt;0.001), including myocardial infarction (HR 1.22; 95% CI 1.01–1.48; &lt;em&gt;p&lt;/em&gt; = 0.045), total stroke (HR 1.18; 95% CI 1.06–1.31; &lt;em&gt;p&lt;/em&gt; = 0.003), and mortality (HR 1.34; 95% CI 1.24–1.46; &lt;em&gt;p &lt;&lt;/em&gt;0.001) in MASLD. Associations were stronger among women (HR 1.17; 95% CI 1.07–1.29; &lt;em&gt;p &lt;&lt;/em&gt;0.01) and physically inactive individuals (HR 1.09; 95% CI 1.05–1.13; &lt;em&gt;p &lt;&lt;/em&gt;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; &lt;em&gt;p &lt;&lt;/em&gt;0.001). Triglyceride-glucose index partially mediated these associations (5.3% for CVD, &lt;em&gt;p&lt;/em&gt; = 0.006; 2.9% for mortality, &lt;em&gt;p&lt;/em&gt; = 0.003), whereas PLT exhibited a slight inverse mediation effect on mortality (-3.3%, &lt;em&gt;p&lt;/em&gt; = 0.032).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;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}

{"title":"Lenvatinib vs. sorafenib as second-line treatment post atezolizumab plus bevacizumab for hepatocellular carcinoma: The LEVIATHAN study","authors":"Pasquale Lombardi ,&nbsp;Jung Sun Kim ,&nbsp;Giulia F. Manfredi ,&nbsp;Ciro Celsa ,&nbsp;Claudia A.M. Fulgenzi ,&nbsp;Antonio D’Alessio ,&nbsp;Bernardo Stefanini ,&nbsp;Niraj C. Doshi ,&nbsp;Emily Warmington ,&nbsp;Thomas U. Marron ,&nbsp;Matthias Pinter ,&nbsp;Bernhard Scheiner ,&nbsp;Beodeul Kang ,&nbsp;Ho Yeong Lim ,&nbsp;Wei-Fan Hsu ,&nbsp;Brooke Wietharn ,&nbsp;Marianna Silletta ,&nbsp;Alessandro Parisi ,&nbsp;Chun-Yen Lin ,&nbsp;Andrea Dalbeni ,&nbsp;David J. Pinato","doi":"10.1016/j.jhepr.2025.101595","DOIUrl":"10.1016/j.jhepr.2025.101595","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In the overall second-line cohort, lenvatinib was associated with superior median progression-free survival (5.5 &lt;em&gt;vs.&lt;/em&gt; 2.6 months, hazard ratio [HR] 0.41, &lt;em&gt;p&lt;/em&gt; &lt;0.001) and median OS (11.9 &lt;em&gt;vs.&lt;/em&gt; 7.4 months, HR 0.67, &lt;em&gt;p&lt;/em&gt; = 0.018) compared to sorafenib. From the start of A+B, the A+B-lenvatinib sequence achieved a median OS of 22.4 months &lt;em&gt;vs.&lt;/em&gt; 14.3 months with A+B-sorafenib (HR 0.54, &lt;em&gt;p&lt;/em&gt; &lt;0.001). These differences persisted in the propensity score-matched cohort (median OS: 19.6 &lt;em&gt;vs.&lt;/em&gt; 13.9 months, HR 0.67, &lt;em&gt;p&lt;/em&gt; = 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 &lt;3, and absence of portal vein thrombosis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;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}

{"title":"Stage-dependent effects of systemic ASBT inhibition in a cholestasis-induced cholemic nephropathy mouse model","authors":"Ahmed Ghallab ,&nbsp;Maiju Myllys ,&nbsp;Daniela González ,&nbsp;Adrian Friebel ,&nbsp;Zaynab Hobloss ,&nbsp;Reham Hassan ,&nbsp;Hannah Schmidt ,&nbsp;Qasim Siddiqui ,&nbsp;Deng Zhipeng ,&nbsp;Rama Hendawi ,&nbsp;Brigitte Begher-Tibbe ,&nbsp;Joerg Reinders ,&nbsp;Katharina Derksen ,&nbsp;Ute Hofmann ,&nbsp;Julia C. Duda ,&nbsp;Lucia Ameis ,&nbsp;Kathrin Möllenhoff ,&nbsp;Abdellatief Seddek ,&nbsp;Noha Abdelmageed ,&nbsp;Ellen Strängberg ,&nbsp;Jan G. Hengstler","doi":"10.1016/j.jhepr.2025.101599","DOIUrl":"10.1016/j.jhepr.2025.101599","url":null,"abstract":"<div><h3>Background &amp; 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> &lt;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}

{"title":"FKBP9 enhances IGF2BP1-mediated m6A recognition to promote hepatocellular carcinoma progression","authors":"Facai Yang ,&nbsp;Anfeng Si ,&nbsp;Cheng Chi ,&nbsp;Weihu Ma ,&nbsp;Yinmin Gu ,&nbsp;Yongbo Pan ,&nbsp;Jingzhan Zhu ,&nbsp;Yigang He ,&nbsp;Xuewu Tang ,&nbsp;Qiushi Yu ,&nbsp;Yanuo Chen ,&nbsp;Tongfeng Liu ,&nbsp;Shan Gao ,&nbsp;Fangliang Xie ,&nbsp;Zhengqing Lei ,&nbsp;Hongping Xia ,&nbsp;Zhangjun Cheng","doi":"10.1016/j.jhepr.2025.101584","DOIUrl":"10.1016/j.jhepr.2025.101584","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>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).</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> &lt;0.05) and correlated with unfavorable clinical outcomes in patients (<em>p</em> &lt;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 <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> &lt;0.05). Co-overexpression of FKBP9 with MYC or PDGFB was linked to a worse prognosis (<em>p</em> &lt;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}

{"title":"A retrospective evaluation of preemptive liver transplantation for bile duct dysplasia in primary sclerosing cholangitis: Balancing risks and benefits","authors":"Sigurd Breder ,&nbsp;Christina Villard ,&nbsp;Emma Eide ,&nbsp;Benny Wang ,&nbsp;Lise Katrine Engesæter ,&nbsp;Henrik Mikael Reims ,&nbsp;Johannes Roksund Hov ,&nbsp;Espen Melum ,&nbsp;Lars Aabakken ,&nbsp;Pål Dag Line ,&nbsp;Jon Lømo ,&nbsp;Krzyztof Grzyb ,&nbsp;Kristine Wiencke ,&nbsp;Annika Bergquist ,&nbsp;Trine Folseraas","doi":"10.1016/j.jhepr.2025.101598","DOIUrl":"10.1016/j.jhepr.2025.101598","url":null,"abstract":"<div><h3>Background &amp; 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}

{"title":"Development of a CRE/CREB-driven HBx responsive HBV cell culture reporter system for antiviral drug evaluation","authors":"Muhammad Atif Zahoor ,&nbsp;Nahla FadlElMawla ,&nbsp;Adrian Kuipery ,&nbsp;Joshua B. Feld ,&nbsp;Avisha Chowdhury ,&nbsp;Alexander I. Mosa ,&nbsp;Adam J. Gehring ,&nbsp;Jordan J. Feld","doi":"10.1016/j.jhepr.2025.101596","DOIUrl":"10.1016/j.jhepr.2025.101596","url":null,"abstract":"<div><h3>Background &amp; 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 &lt;</em>0.0001). HBV infection with both culture-derived and patient-derived clinical isolates (genotypes A-E) significantly increased luciferase activity (<em>p &lt;</em>0.0001). Treatment with HBx inhibitors (siRNA, specific HBx inhibitors), as well as IFNα reduced luciferase production (<em>p &lt;</em>0.0001). In contrast, antivirals that do not interfere with protein production (tenofovir), or viral entry (bulevirtide) showed no effect (<em>p &lt;</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}

{"title":"PD-L1 and the risk of bacterial infection in patients with chronic liver diseases: An international multicohort study","authors":"Adrià Juanola ,&nbsp;Gabriel Mezzano ,&nbsp;Elisa Pose ,&nbsp;Maria J. Moreta ,&nbsp;Simone Incicco ,&nbsp;Roberta Gagliardi ,&nbsp;Stine Johansen ,&nbsp;Nikolaj Torp ,&nbsp;Mads Israelsen ,&nbsp;Natalia Jiménez-Esquivel ,&nbsp;Joaquin Castillo-Iturra ,&nbsp;Jordi Ribera ,&nbsp;Jordi Gratacós-Ginès ,&nbsp;Anna Soria ,&nbsp;Andrés Cárdenas ,&nbsp;Martina Pérez-Guasch ,&nbsp;Marta Cervera ,&nbsp;Ruth Nadal ,&nbsp;Queralt Herms ,&nbsp;Marta Tonon ,&nbsp;Pere Ginès","doi":"10.1016/j.jhepr.2025.101597","DOIUrl":"10.1016/j.jhepr.2025.101597","url":null,"abstract":"<div><h3>Background &amp; 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 &lt;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 &lt;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}

{"title":"Disparities in transplant access and outcomes after first cirrhosis decompensation in alcohol-related liver disease","authors":"José Ursic Bedoya ,&nbsp;Charlotte De Choudens ,&nbsp;Margaux Delhomme ,&nbsp;Astrid Herrero ,&nbsp;Stéphanie Faure ,&nbsp;Lucy Meunier ,&nbsp;Magdalena Meszaros ,&nbsp;Georges-Philippe Pageaux ,&nbsp;Claire Duflos","doi":"10.1016/j.jhepr.2025.101594","DOIUrl":"10.1016/j.jhepr.2025.101594","url":null,"abstract":"<div><h3>Background &amp; 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> &lt;0.0001), as were women (HR 0.75, 95% CI 0.69–0.81, <em>p</em> &lt;0.0001), patients with solidarity-based health insurance (HR 0.82, 95% CI 0.74–0.90, <em>p</em> &lt;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}