JHEP Reports最新文献

{"title":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(26)00113-8","DOIUrl":"10.1016/S2589-5559(26)00113-8","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 4","pages":"Article 101842"},"PeriodicalIF":7.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147656627","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":"Cell-SELEX identifies a DNA aptamer for highly selective in vivo siRNA delivery in cholangiocarcinoma","authors":"Brandon A. Wilbanks ,&nbsp;Ayano Kabashima ,&nbsp;Enis H. Ozmert ,&nbsp;Jack W. Sample ,&nbsp;Julia Driscoll ,&nbsp;Danielle M. Carlson ,&nbsp;Caroline D. Doherty ,&nbsp;Brooke Kimball ,&nbsp;Jayla Millender ,&nbsp;Irene K. Yan ,&nbsp;Hidemi Nishi ,&nbsp;Piyush Gondaliya ,&nbsp;Keenan S. Pearson ,&nbsp;Gregory J. Gores ,&nbsp;Tushar Patel ,&nbsp;L. James Maher III ,&nbsp;Rory L. Smoot","doi":"10.1016/j.jhepr.2026.101779","DOIUrl":"10.1016/j.jhepr.2026.101779","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Systematic evolution of ligands by exponential enrichment (SELEX) is a powerful technology for selecting tumor-targeting DNA aptamers from vast pools of trillions of randomly synthesized candidates. We aimed to apply SELEX to identify aptamers capable of selectively delivering therapeutic payloads to murine and human cholangiocarcinoma (CCA). We tested whether this approach enables delivery of small-interfering RNA (siRNA) therapies to knockdown otherwise undruggable oncogene targets.</div></div><div><h3>Methods</h3><div>We performed 11 rounds of cell-SELEX targeting the human cholangiocarcinoma cell line HuCCT1, with alternating negative selection against normal hepatocytes and cholangiocytes. Over 600 trillion molecules were screened for selective binding, and the specificity of the top aptamer candidate was validated through <em>in vitro</em> binding assays and <em>in vivo</em> biodistribution experiments in mice. Aptamer-guided nanovesicles were loaded with siRNAs targeting undruggable oncogenes and administered to animals bearing orthotopic CCA tumors in a 2-week treatment regimen.</div></div><div><h3>Results</h3><div>DNA Aptamer 1 selectively bound to CCA cells compared with non-target tissues. Tumor localization of Aptamer 1 was 23-fold higher than liver (<em>p</em> = 0.014), over 6-fold higher than lung (<em>p</em> = 0.004) and heart (<em>p</em> = 0.028), and nearly 3-fold higher than kidneys (<em>p</em> = 0.011). This favorable biodistribution enabled tumor-targeted siRNA delivery via incorporation of Aptamer 1 into the membrane of previously described fusogenic nanovesicles. Tumor protein expression was reduced by 70% or more for three oncogenic targets – YAP (<em>p</em> &lt;0.001), TAZ (<em>p</em> = 0.047), and LCK (<em>p =</em> 0.021) – in orthotopically implanted CCA tumors, with no corresponding knockdown in surrounding liver tissue.</div></div><div><h3>Conclusion</h3><div>SELEX identified a novel DNA aptamer enabling tumor-selective delivery of therapeutic payloads against three oncogenes considered to be undruggable. This is a promising advance towards a treatment strategy that has not yet been explored for CCA.</div></div><div><h3>Impact and implications</h3><div>Platforms for highly tumor-selective delivery of small-interfering RNAs (siRNAs) have the potential to unlock new therapeutic strategies targeting oncogenic proteins previously considered undruggable. SELEX facilitates the identification of DNA aptamers with tumor-specific binding, enabling such approaches. Here, we describe the selection of a novel tumor-targeting aptamer that mediates precise delivery of siRNA-loaded nanovesicles to tumors. These findings represent a significant advance in aptamer-guided, tumor-selective nanovesicle delivery and highlight the potential of this platform for further development toward clinical application.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 4","pages":"Article 101779"},"PeriodicalIF":7.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638830","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":"Elebsiran and pegylated-IFNα: Progress toward a functional cure for chronic hepatitis B","authors":"Sara Battistella ,&nbsp;Ulrike Protzer ,&nbsp;Xavier Forns","doi":"10.1016/j.jhepr.2026.101741","DOIUrl":"10.1016/j.jhepr.2026.101741","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 4","pages":"Article 101741"},"PeriodicalIF":7.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638870","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":"Gene-environment “amplification” of liver stiffness requires more clinically meaningful analytic approaches","authors":"Yiran Zhang ,&nbsp;Qing Xie ,&nbsp;Zhujun Cao","doi":"10.1016/j.jhepr.2025.101690","DOIUrl":"10.1016/j.jhepr.2025.101690","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101690"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377529","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":"Mycobiome dysbiosis and genetic predisposition to elevated IL-17A contribute to fibrosis in MASLD","authors":"Nadja Thielemann ,&nbsp;Sara Leal Siliceo ,&nbsp;Monika Rau ,&nbsp;Annika Schöninger ,&nbsp;Nathalie Reus ,&nbsp;Alexander M. Aldejohann ,&nbsp;Aia Shehata ,&nbsp;Isabell S. Behr ,&nbsp;Natalie E. Nieuwenhuizen ,&nbsp;Michaela Herz ,&nbsp;Heike M. Hermanns ,&nbsp;Mohammad Mirhakkak ,&nbsp;Jürgen Löffler ,&nbsp;Thomas Dandekar ,&nbsp;Kerstin Hünniger-Ast ,&nbsp;Ronny Martin ,&nbsp;Gianni Panagiotou ,&nbsp;Andreas Geier ,&nbsp;Oliver Kurzai","doi":"10.1016/j.jhepr.2025.101721","DOIUrl":"10.1016/j.jhepr.2025.101721","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in Western countries. Progression to metabolic dysfunction-associated steatohepatitis (MASH) occurs when fat accumulation in the liver triggers inflammatory processes including T helper 17 cell (Th17) activation. We aimed to investigate the role of intestinal fungi in MASH-mediating Th17-signaling.</div></div><div><h3>Methods</h3><div>Blood samples from patients with MASLD (n = 451), including 141 with histology-proven MASH, were genotyped for <em>IL17A</em> rs2275913. Microbiome composition was assessed by ITS1 and 16S rRNA sequencing of stool samples from patients with MASLD (n = 221), including 79 with histology-proven MASH, as well as 25 healthy controls. Highly abundant fungal species identified in patients with MASH were used to stimulate <em>IL17A</em> rs2275913–genotyped T cells <em>ex vivo</em>, and cytokine levels were measured (n = 9 per genotype). Th17/resting regulatory T cell (Th17/rTreg) ratios were analyzed in relation to <em>IL17A</em> rs2275913 genotype in patients with MASLD (n = 58), including 31 with histology-proven MASH, and 28 healthy controls.</div></div><div><h3>Results</h3><div>We identified the <em>IL17A</em> rs2275913 minor allele variant as a risk factor for fibrosis progression in patients with MASLD. In patients with advanced fibrosis, we also observed an increased abundance of fungal CTG species, including <em>Candida albicans</em> and <em>Debaryomyces hansenii</em>, which are potent triggers of Th17 responses. Integrating genetic predisposition with mycobiome composition, <em>ex vivo</em> T-cell stimulation assays demonstrated that donors carrying the <em>IL17A</em> rs2275913 minor allele secreted significantly higher levels of IL-17A in response to CTG species. Additionally, patients with MASH carrying the <em>IL17A</em> rs2275913 risk allele had elevated Th17/Treg ratios in peripheral blood.</div></div><div><h3>Conclusions</h3><div>Genetic predisposition to enhanced Th17 responses, in the context of mycobiome dysbiosis, may promote MASH progression and liver fibrosis.</div></div><div><h3>Impact and implications</h3><div>Liver inflammation and fibrosis are key drivers of the transition from bland steatosis to metabolic dysfunction-associated steatohepatitis (MASH). Our findings identify a combinatorial mechanism in which genetic predisposition to enhanced IL-17A signaling, together with gut mycobiome dysbiosis, promotes MASH development and fibrosis progression. This work highlights the importance of host–mycobiome interactions in shaping inflammatory liver disease and supports further investigation into targeted strategies aimed at modulating IL-17A–mediated immune responses in patients with MASLD. Such approaches may offer novel opportunities for risk stratification and therapeutic intervention.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101721"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226819","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":"Multidrug-resistant colonization in decompensated cirrhosis outside the ICU predicts infection and poor outcomes","authors":"María Hernández-Tejero ,&nbsp;Marco Pavesi ,&nbsp;Fátima Aziz ,&nbsp;Nini Johana Bustos ,&nbsp;Santiago Ortiz ,&nbsp;Foix Vallès ,&nbsp;Berta López-Sáez ,&nbsp;Juan Manuel Díaz ,&nbsp;Cristina Pitart ,&nbsp;Ester López ,&nbsp;Mary Torrance ,&nbsp;Alex Soriano ,&nbsp;Jordi Vila ,&nbsp;José Antonio Martínez ,&nbsp;Francesc Marco ,&nbsp;Javier Fernández","doi":"10.1016/j.jhepr.2025.101707","DOIUrl":"10.1016/j.jhepr.2025.101707","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Infections caused by multidrug- (MDROs) or extensively drug- (XDROs) resistant organisms are an increasing global concern in cirrhosis. While MDRO colonization is a recognized risk factor for infection in critical care settings, evidence in ward-based patients with decompensated cirrhosis is limited. This study aimed to determine the prevalence, dynamics, and clinical impact of MDRO colonization outside the intensive care unit (ICU) and to identify predictors of colonization and infection.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a single-center prospective study (2017–2020) enrolling 408 patients with decompensated cirrhosis consecutively admitted to the ward (n = 272) or ICU (n = 136). Rectal and nasal swabs were obtained at admission and weekly for up to 12 months. Colonization dynamics, resistance profiles, infection rates, and outcomes were analyzed in ward patients, with the ICU cohort serving as a comparator.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Baseline rectal MDRO colonization was common in both the ward and ICU (23% &lt;em&gt;vs.&lt;/em&gt; 17%; &lt;em&gt;p =&lt;/em&gt; 0.38) and increased over time, reaching similar rates at 1 year (39% &lt;em&gt;vs.&lt;/em&gt; 43%; &lt;em&gt;p =&lt;/em&gt; 0.13). XDROs emerged during follow-up in both settings. In ward patients, baseline (52% &lt;em&gt;vs.&lt;/em&gt; 19%; &lt;em&gt;p &lt;&lt;/em&gt;0.0001) or follow-up (55% &lt;em&gt;vs.&lt;/em&gt; 11%; &lt;em&gt;p &lt;&lt;/em&gt;0.0001) colonization was associated with MDRO infection by the colonizing strain and with higher mortality (60% &lt;em&gt;vs.&lt;/em&gt; 22%; &lt;em&gt;p &lt;&lt;/em&gt;0.0001). Baseline (hazard ratio [HR] 9.6; &lt;em&gt;p &lt;&lt;/em&gt;0.0001) and follow-up colonization (HR 4.4; &lt;em&gt;p &lt;&lt;/em&gt;0.0001) independently predicted infection, and colonization at either time point predicted mortality (HR 2.07; &lt;em&gt;p &lt;&lt;/em&gt;0.0001). Recent acute-on-chronic liver failure predicted colonization (HR 2.5; &lt;em&gt;p &lt;&lt;/em&gt;0.0001) and infection (HR 2.8; &lt;em&gt;p =&lt;/em&gt; 0.0003).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;MDRO colonization is frequent and clinically significant outside the ICU in patients with cirrhosis, predicting both infection and mortality. Extending targeted surveillance and antibiotic stewardship beyond critical care may help reduce infection-related morbidity and mortality.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;This study demonstrates that rectal colonization with multidrug-resistant organisms is both common and clinically significant in patients with decompensated cirrhosis outside the intensive care unit. These findings are highly relevant for hepatologists, infectious disease clinicians, and epidemiologists, as colonized ward patients faced a substantially increased risk of developing infections from their colonizing strain and experienced worse outcomes, particularly those with recent acute-on-chronic liver failure. Practically, incorporating colonization status into empirical antibiotic decision-making and evaluating targeted multidrug-resistant organism surveillance strategies beyon","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101707"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147271135","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":"Fibrosis activity vs. disease stage: Complementary and independent predictors of outcomes in alcohol-related liver disease","authors":"Stine Johansen ,&nbsp;Mads Israelsen ,&nbsp;Katrine Holtz Thorhauge ,&nbsp;Johanne Kragh Hansen ,&nbsp;Camilla Dalby Hansen ,&nbsp;Helle Lindholm Schnefeld ,&nbsp;Peter Andersen ,&nbsp;Ida Villesen ,&nbsp;Katrine Tholstrup Bech ,&nbsp;Sönke Detlefsen ,&nbsp;Nikolaj Torp ,&nbsp;Diana Leeming ,&nbsp;Maja Thiele ,&nbsp;Aleksander Krag ,&nbsp;Morten Karsdal ,&nbsp;GALAXY consortia","doi":"10.1016/j.jhepr.2026.101746","DOIUrl":"10.1016/j.jhepr.2026.101746","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Excessive alcohol consumption accelerates fibrosis progression in steatotic liver disease. Disease activity can be described by fibrogenic activity, of which collagen formation is a central process. Type III collagen formation (PRO-C3) is a biomarker of fibrosis activity. We aimed to evaluate whether PRO-C3 predicts clinical outcomes in alcohol-related liver disease (ALD) independent of fibrosis stage.</div></div><div><h3>Methods</h3><div>We conducted a prospective cohort study including patients with prior or current excessive alcohol intake (men: ≥36 g/day; women: ≥24 g/day for &gt;1 year) and no prior decompensation. At baseline, liver biopsies, clinical investigations, and non-invasive blood tests were performed. During follow-up, patients’ electronic healthcare records were manually reviewed for decompensation events and all-cause mortality. Decompensation was defined according to Baveno VII recommendations.</div></div><div><h3>Results</h3><div>We followed 458 patients with ALD (76% male; mean age 57 ± 10 years) for a median of 5.9 years (IQR 4.5–7.8). At baseline, fibrosis stages were F0–1 (n = 260), F2 (n = 107), and F3-4 (n = 91). During follow-up, 67 patients experienced decompensation and 100 died. PRO-C3 provided prognostic value beyond fibrosis stage as a predictor of decompensation, both in patients with no to moderate fibrosis (F0-2; subhazard ratio per unit increase in PRO-C3 1.05; 95% CI 1.03–1.07; <em>p</em> &lt;0.001) and in patients with cirrhosis (F4; subhazard ratio 1.01; 95% CI 1.00–1.03; <em>p</em> = 0.048).</div></div><div><h3>Conclusions</h3><div>In ALD, prognosis is determined by both baseline fibrosis stage and markers of fibrosis activity. PRO-C3, a biomarker of fibrosis activity, was more strongly associated with the risk of decompensation than Kleiner fibrosis stage and predicted decompensation across fibrosis stages.</div></div><div><h3>Impact and implications</h3><div>This study shows that fibrosis activity measured by PRO-C3 captures dynamic disease processes in alcohol-related liver disease that are not fully reflected by histological fibrosis stage. These findings are important for clinicians and patients because PRO-C3 independently predicts decompensation and supports stratifying risk by fibrosis activity in addition to stage. Practically, incorporating fibrosis-activity biomarkers could guide earlier monitoring and interventions aimed at modulating fibrogenic activity.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101746"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283620","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":"Factors associated with protection from MASLD in type 2 diabetes: A prospective study integrating longitudinal MRI/MRE and stable isotope tracing","authors":"Federica Tavaglione ,&nbsp;Veeral Ajmera ,&nbsp;Luis Antonio Díaz ,&nbsp;Kelvin Li ,&nbsp;Egbert Madamba ,&nbsp;Ricki Bettencourt ,&nbsp;Lisa Richards ,&nbsp;Marc Hellerstein ,&nbsp;Rohit Loomba","doi":"10.1016/j.jhepr.2026.101733","DOIUrl":"10.1016/j.jhepr.2026.101733","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Type 2 diabetes is one of the strongest risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we aimed to identify factors associated with protection from MASLD in a prospective cohort of individuals with type 2 diabetes.</div></div><div><h3>Methods</h3><div>This prospective study included 148 individuals with type 2 diabetes who underwent advanced liver phenotyping using MRI and MRE techniques at baseline and 2-year follow-up. Protection from MASLD was defined as the absence of hepatic steatosis (MRI-proton density fat fraction &lt;5%) and significant fibrosis (MRE &lt;3 kPa) at both time points. Factors associated with protection from MASLD were assessed using Firth’s penalized logistic regression. Regularized logistic regression models were fitted as complementary analyses.</div></div><div><h3>Results</h3><div>The mean (SD) age and BMI were 65 (8) years and 30.4 (4.3) kg/m², respectively. After a median follow-up of 2 (1.5–2.4) years, 27 (18%) individuals demonstrated an absence of MASLD. Across all modeling approaches, lower BMI (odds ratio [OR] 0.81, 95% CI 0.64–0.98; <em>p =</em> 0.029), lower HOMA-IR (OR 0.59, 95% CI 0.39–0.83; <em>p =</em> 8.6e-4), and lower circulating triglycerides (OR 0.986, 95% CI 0.973–0.997; <em>p =</em> 0.011) emerged as the strongest predictors of protection from MASLD. An exploratory analysis of 11 individuals with type 2 diabetes from an independent cohort, with hepatic <em>de novo</em> lipogenesis quantified by stable isotope tracing, revealed lower hepatic <em>de novo</em> lipogenesis in those free from MASLD.</div></div><div><h3>Conclusions</h3><div>Managing modifiable risk factors, such as body weight and lipid profile, may be critical for preventing MASLD development in individuals with type 2 diabetes.</div></div><div><h3>Impact and implications</h3><div>Understanding factors conferring protection from metabolic dysfunction-associated steatotic liver disease (MASLD) in individuals with type 2 diabetes represents a novel research avenue which has not been systematically explored. In this prospective cohort of 148 individuals with type 2 diabetes undergoing advanced liver phenotyping at baseline and 2-year follow-up, we identified lower BMI, lower HOMA-IR, and lower circulating triglycerides as the strongest predictors of remaining free of MASLD. Additionally, by performing an exploratory analysis in an independent cohort of 11 individuals with type 2 diabetes with tracer data, we found that lower hepatic <em>de novo</em> lipogenesis may underlie this protective phenotype. These findings suggest that managing modifiable risk factors, such as body weight and lipid profile, may be critical for preventing MASLD development and progression in individuals with type 2 diabetes.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101733"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carvedilol decreases hepatic vascular resistance by reducing fibrogenesis and reversing endothelial dysfunction in cirrhotic rats","authors":"Yeldos Nulan ,&nbsp;Eric Felli ,&nbsp;Sonia-Emilia Selicean ,&nbsp;Manuel Prampolini ,&nbsp;Annalisa Berzigotti ,&nbsp;Jordi Gracia-Sancho ,&nbsp;Jaume Bosch","doi":"10.1016/j.jhepr.2025.101681","DOIUrl":"10.1016/j.jhepr.2025.101681","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Cirrhosis increases hepatic vascular resistance (IHVR) by disrupting liver architecture due to fibrosis, and by elevating hepatic vascular tone due to hepatic endothelial dysfunction. IHVR increases portal pressure (PP), later aggravated by increased portal blood inflow. Carvedilol, a third-generation non-selective β-blocker with anti-α1-adrenergic activity, reduces PP more than propranolol, likely decreasing IHVR. However, its intrahepatic effects remain largely unexplored. This study aimed to address these issues.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Human cell lines (LX2 and HUVECs) and primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) isolated from cirrhotic rats (12-week thioacetamide [TAA] model) were treated with vehicle, carvedilol (10 μM), or propranolol (10 μM). Nitric oxide release, oxidative stress, and cell contraction were assessed. Cirrhotic rats were treated with vehicle, carvedilol (10 mg/kg/day for 2 weeks), or propranolol (30 mg/kg/day for 2 weeks) at early and advanced stages of cirrhosis (9 and 12 weeks of TAA). Hepatic hemodynamics, liver fibrosis, antioxidant activity, and inflammatory biomarkers were evaluated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Carvedilol increased nitric oxide release in LSECs and HUVECs and significantly reduced contraction of HSCs and LX2 cells in cirrhotic conditions. &lt;em&gt;In vivo&lt;/em&gt;, carvedilol significantly reduced PP in both early and advanced cirrhosis (12-week TAA: −22%, &lt;em&gt;p =&lt;/em&gt; 0.0008; 9-week TAA: −17%, &lt;em&gt;p =&lt;/em&gt; 0.0038), decreased liver fibrosis area (−26.8%, &lt;em&gt;p =&lt;/em&gt; 0.0013 &lt;em&gt;vs.&lt;/em&gt; −23.1%, &lt;em&gt;p =&lt;/em&gt; 0.0047), and reduced α-SMA expression (−22.7%, &lt;em&gt;p =&lt;/em&gt; 0.0018 &lt;em&gt;vs.&lt;/em&gt; −17.4%, &lt;em&gt;p =&lt;/em&gt; 0.0455). Additionally, carvedilol improved endothelial dysfunction and reduced oxidative stress and inflammation. Propranolol did not exert these beneficial effects and produced a smaller, non-significant reduction in PP (−7%, &lt;em&gt;p =&lt;/em&gt; 0.4029).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The greater reduction in PP achieved with carvedilol is mediated not only by its non-selective β-blocker effects but, more importantly, by its ability to reverse hepatic endothelial dysfunction, reduce fibrosis, enhance antioxidant activity, and exert moderate anti-inflammatory effects. These findings support extending the use of carvedilol even to patients without overt signs of portal hypertension.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Carvedilol is considered the best β-blocker for treating portal hypertension. In this study we show that carvedilol, unlike traditional β-blockers such as propranolol, downregulates the factors that lead to increased portal pressure in cirrhosis: it lowers the hepatic vascular tone by counteracting hepatic sinusoidal endothelial dysfunction, and decreases liver fibrosis by deactivating hepatic stellate cells and inhibiting their proliferation. On top of decreasing portal","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101681"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077000","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":"Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study","authors":"Ciro Celsa ,&nbsp;Tiziana Pressiani ,&nbsp;Naoshi Nishida ,&nbsp;Shadi Mohamad Chamseddine ,&nbsp;Ashwini Arvind ,&nbsp;Michael Li ,&nbsp;Marta Fortuny ,&nbsp;Najib Ben Khaled ,&nbsp;Massimo Iavarone ,&nbsp;Hidenori Toyoda ,&nbsp;Ilario Giovanni Rapposelli ,&nbsp;Andrea Casadei-Gardini ,&nbsp;Caterina Vivaldi ,&nbsp;Susanna Ulahannan ,&nbsp;Haripriya Andanamala ,&nbsp;Bernhard Scheiner ,&nbsp;Matthias Pinter ,&nbsp;Elena Orlandi ,&nbsp;Claudia A.M. Fulgenzi ,&nbsp;Giulia F. Manfredi ,&nbsp;David James Pinato","doi":"10.1016/j.jhepr.2025.101685","DOIUrl":"10.1016/j.jhepr.2025.101685","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Durvalumab plus tremelimumab (STRIDE) has emerged as a first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC). This international multicentre study aimed to evaluate the efficacy and tolerability of STRIDE or durvalumab monotherapy in routine clinical practice, comparing outcomes between patients within and outside key eligibility criteria for the HIMALAYA trial.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;From a database of 1,423 patients with advanced/unresectable HCC treated with immunotherapy across 35 centres, we analysed 233 patients receiving STRIDE or durvalumab monotherapy. Patients were categorized as HIMALAYA-IN or HIMALAYA-OUT based on key trial eligibility criteria (no prior systemic therapy, ECOG-PS 0–1, Child-Pugh class A, no Vp4 thrombosis). Baseline characteristics were assessed for overall survival (OS) and hepatic decompensation using a multivariable Cox model and competing-risk analysis, respectively. Objective response rates and treatment-related adverse events were recorded.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Of the 233 patients, 123 (53%) were HIMALAYA-IN and 110 (47%) were HIMALAYA-OUT. STRIDE was given in 95% of HIMALAYA-IN patients. After median follow-up of 6.0 months, median OS was 20.4 months (95% CI 11.7-NR) in the overall population. HIMALAYA-IN patients achieved significantly longer OS than HIMALAYA-OUT patients (23.0 &lt;em&gt;vs.&lt;/em&gt; 12.2 months; hazard ratio 0.61; 95% CI 0.39-0.96; &lt;em&gt;p&lt;/em&gt; = 0.03). Macrovascular invasion and hepatic decompensation were independent negative prognostic factors in the whole cohort. Hepatic decompensation occurred in 10.5% of patients within 12 months from treatment start. Objective response rate was 23.7% and 17.8% of HIMALAYA-IN and -OUT patients, respectively. Patients achieving disease control (whole cohort: 59.4%) demonstrated 24-month OS of 58.2% in HIMALAYA-IN and 44.8% in HIMALAYA-OUT groups. Grade 3-4 treatment-related adverse events occurred in 16.3% of patients.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;STRIDE shows reproducible effectiveness and an acceptable safety profile in real-world practice. Achieving disease control and maintaining liver function emerged as key determinants of long-term survival benefit.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;The DT-real study validates the efficacy and safety of STRIDE (durvalumab plus tremelimumab) in routine clinical practice, with HIMALAYA trial-eligible patients achieving 23-month median survival, and showing a safety profile comparable to that observed in the pivotal trial. Nearly half of real-world patients received treatment despite not meeting original trial criteria, reflecting urgent clinical need in this population with limited therapeutic options. As for other immunotherapy-based combinations, hepatic decompensation is a critical determinant of survival. Patients achieving disease control demonstrated substantially improved 24-month overall su","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101685"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165369","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}