JHEP Reports最新文献

{"title":"Enhanced nuclear localization of small heterodimer partner in metabolic dysfunction-associated steatohepatitis","authors":"Shih-Chieh Chien ,&nbsp;Chiung-Yu Chen ,&nbsp;Hung-Wen Tsai ,&nbsp;Yih-Jyh Lin ,&nbsp;Shu-Chu Shiesh ,&nbsp;Pin-Nan Cheng ,&nbsp;Hung-Chih Chiu ,&nbsp;Yen-Cheng Chiu ,&nbsp;Ya-Han Lin ,&nbsp;Min-Shan Wu ,&nbsp;Mei-Juan Zheng ,&nbsp;Kung-Chia Young ,&nbsp;Yau-Sheng Tsai","doi":"10.1016/j.jhepr.2025.101616","DOIUrl":"10.1016/j.jhepr.2025.101616","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The nuclear factor small heterodimer partner (SHP) plays a dual function in maintaining bile acid (BA) homeostasis and exerting anti-inflammatory effects. While SHP might be associated with metabolic dysfunction-associated steatohepatitis (MASH), its role in patients remains unclear.</div></div><div><h3>Methods</h3><div>Liver tissue and serum samples were collected from 69 patients with MASH and 10 healthy controls. The subcellular distribution of SHP and related proteins in liver tissue were analyzed to correlate with MASH-associated pathological characteristics. <em>In vitro</em> studies were conducted to elucidate the underlying mechanisms and clinical relevance of SHP nuclear translocation in MASH.</div></div><div><h3>Results</h3><div>Compared with controls, patients with MASH demonstrated a higher nuclear SHP ratio (51.7% <em>vs.</em> 1.55%, <em>p</em> &lt;0.001), which correlated with the severity of hepatitis and steatosis, but not with serum BA levels. The nuclear SHP ratio increased in parallel with atypical protein kinase C zeta (PKCζ) signal intensity and showed high co-localization with nucleoporin RanBP2. <em>In vitro</em> experiments demonstrated that both toxic fatty acid and inflammatory cytokine could induce SHP nuclear translocation, which was blocked by PKCζ inhibition. <em>SHP</em> knockdown increased basal innate immune activity, accelerated intracellular lipid accumulation, and recapitulated a MASH-like gene profile that facilitates BA accumulation.</div></div><div><h3>Conclusions</h3><div>Nuclear SHP accumulation is a distinctive feature of MASH pathology. This PKCζ-dependent process may exert anti-inflammation and anti-cholestasis function in patients with MASH.</div></div><div><h3>Impact and implications</h3><div>The nuclear factor small heterodimer partner (SHP) plays a dual role in maintaining bile acid homeostasis and suppressing inflammation. In patients with metabolic dysfunction-associated steatohepatitis (MASH), we identified a pathological increase in the hepatocellular nuclear SHP ratio, likely triggered by lipid overload and inflammatory stimuli, and dependent on PKCζ activation. <em>SHP</em> knockdown <em>in vitro</em> induced cellular steatosis, innate immune responses, and leading to a cholestatic gene expression profile. These findings highlight SHP as a potential therapeutic target in MASH.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101616"},"PeriodicalIF":7.5,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682290","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":"3D endothelial cell scaffolds protect liver explants and exhibit therapeutic effects on liver fibrosis","authors":"Mireia Medrano-Bosch ,&nbsp;Alazne Moreno-Lanceta ,&nbsp;Blanca Simón-Codina ,&nbsp;David Saavedra-Pérez ,&nbsp;Yiliam Fundora ,&nbsp;Francisco J. Sánchez ,&nbsp;Meritxell Perramón ,&nbsp;Laura Macias-Muñoz ,&nbsp;Manuel Morales-Ruiz ,&nbsp;Elazer R. Edelman ,&nbsp;Wladimiro Jiménez ,&nbsp;Pedro Melgar-Lesmes","doi":"10.1016/j.jhepr.2025.101617","DOIUrl":"10.1016/j.jhepr.2025.101617","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Endothelial cells (ECs) display myriad protective roles that support tissue homeostasis. Embedding healthy ECs in 3D scaffolds stabilizes their phenotype to maximize reparative effects and shields immunogenicity. Here, we evaluate the protective effects of matrix-embedded ECs (MEECs) in liver explants and models of chronic liver disease.</div></div><div><h3>Methods</h3><div>Precision cut liver slices (PCLS) from patients with cirrhosis (n = 8) and fibrotic or healthy mice (n = 6) were co-cultured with MEECs for 24 h and hepatic viability and inflammation were analyzed. The protective effects of the MEECs secretome were explored <em>in vitro</em>. MEECs were perihepatically or subcutaneously implanted for 1 week in fibrotic mice with or without hepatectomy (n = 6) to evaluate their effects on liver inflammation, regeneration, and fibrosis.</div></div><div><h3>Results</h3><div>MEECs protected liver viability in PCLS from patients with cirrhosis (ATP/protein, 2.7 <em>vs.</em> 5.0, <em>p</em> = 0.01) and fibrotic (5.3 <em>vs.</em> 7.1, <em>p</em> = 0.01) or healthy (7.8 <em>vs.</em> 10.6, <em>p</em> = 0.01) mice, and reduced injury-induced inflammation. MEECs produced hepatocyte growth factor and fibroblast growth factor 2, which were associated with improved hepatic viability and anti-inflammatory macrophage polarization, respectively. Perihepatic implantation of MEECs in fibrotic mice with or without hepatectomy reduced inflammation and hepatic damage and exhibited pro-regenerative and antifibrotic properties (Sirius red⁺ area, 8.3 <em>vs.</em> 6.4, <em>p</em> = 0.005). These antifibrotic effects were associated with higher production of heparan sulfate and metalloproteinases 2 and 9, and mitigation of hepatic stellate cell activation. Implantation of MEECs at a distance from the liver did not reduce liver injury, inflammation, or fibrosis.</div></div><div><h3>Conclusions</h3><div>Endothelial–hepatocyte regulation is essential in liver repair, and matrix-embedded endothelial cells (MEECs) appear to be a potential therapy for chronic liver injury and <em>ex situ</em> preservation of liver grafts.</div></div><div><h3>Impact and implications</h3><div>Organ transplantation is the most effective therapy for advanced liver disease, yet remains limited by preservation of harvested graft viability and injury-induced inflammation post implantation. Healthy ECs display myriad protective roles that contribute to tissue homeostasis. In this study, we show how MEECs preserve cell viability and reduce inflammation in hepatic explants and display anti-inflammatory, antifibrotic and pro-regenerative properties in the liver of fibrotic mice. These dynamic and unique hepatoprotective properties of MEECs highlight their potential therapeutic utility for chronic liver injury or <em>ex situ</em> conservation of liver grafts.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101617"},"PeriodicalIF":7.5,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682286","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":"Failure-to-rescue as a determinant of overall survival following resection for perihilar cholangiocarcinoma","authors":"Yawen Dong ,&nbsp;Zhihao Li ,&nbsp;Vanja Podrascanin ,&nbsp;John E. Eaton ,&nbsp;Sumera I. Ilyas ,&nbsp;Gregory J. Gores ,&nbsp;Susanne G. Warner ,&nbsp;David M. Nagorney ,&nbsp;Rory L. Smoot ,&nbsp;Patrick P. Starlinger","doi":"10.1016/j.jhepr.2025.101615","DOIUrl":"10.1016/j.jhepr.2025.101615","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Perihilar cholangiocarcinoma (pCCA) is a surgically challenging malignancy associated with a high risk of postoperative complications. However, advances in surgical techniques, perioperative care, and systemic therapy might have improved overall survival (OS) over time. This study investigated the evolving impact of failure-to-rescue (FTR) rates and oncological treatment strategies on outcomes in patients with pCCA after curative surgery.</div></div><div><h3>Methods</h3><div>Patients undergoing curative-intent resection for pCCA at the Mayo Clinic between 2000 and 2024 were retrospectively reviewed. Clinicopathological features were compared across three surgical eras. OS and recurrence-free survival (RFS) were assessed using Kaplan-Meier analysis, with direct matching applied to account for baseline differences.</div></div><div><h3>Results</h3><div>Among 207 resected patients, 28% were operated on between 2000 and 2010, 35.3% between 2011 and 2017, and 36.7% between 2018 and 2024. The most recent cohort had higher rates of extended hepatectomy, vascular resection, and adjuvant therapy. Although the rate of major complications increased from 36.2% to 40.8%, FTR decreased substantially, from 29.2% to 9.7% (<em>p</em> = 0.066), with a concurrent reduction in 90-day mortality from 12.1% to 3.9% (<em>p</em> = 0.076). Median OS significantly improved over time (from 34.8 to 54.7 months; not reached in 2018–2024, <em>p</em> = 0.019), although this trend was no longer significant after excluding 90-day mortality (<em>p</em> = 0.081). Patients receiving adjuvant therapy had better OS (<em>p</em> = 0.042), but the benefit diminished when 90-day mortality was excluded.</div></div><div><h3>Conclusions</h3><div>Improved OS after pCCA resection appears to be primarily driven by reduced FTR, despite greater surgical complexity. Effective perioperative management and the ability to rescue patients from major complications remain the key determinants of survival improvement.</div></div><div><h3>Impact and implications</h3><div>While OS in pCCA has improved over recent decades, it remains a malignancy of high surgical complexity and perioperative risk. Our study identified the reduction in FTR as the key determinant of improved outcomes, driven by increased use of rescue strategies and a shift from surgical to non-operative interventions. Although adjuvant therapy became more common over time and contributed to survival gains, its benefit diminished after adjusting for early postoperative mortality. Meanwhile, the declining rate of dropouts further reflects advances in diagnostics and patient selection, emphasizing the importance of multidisciplinary, centralized care in pCCA management.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101615"},"PeriodicalIF":7.5,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569426","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":"ESMO-MCBS v2.0: Advances, challenges, and perspectives in the assessment of clinical benefit in oncology","authors":"Ezequiel Mauro ,&nbsp;Miquel Serra-Burriel","doi":"10.1016/j.jhepr.2025.101553","DOIUrl":"10.1016/j.jhepr.2025.101553","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101553"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266652","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":"Erratum to: “Liver resection and transplantation in the era of checkpoint inhibitors” JHEP Reports 2024 doi: 10.1016/j.jhepr.2024.101181","authors":"Parissa Tabrizian ,&nbsp;Rebecca Marino ,&nbsp;Pierce K.H. Chow","doi":"10.1016/j.jhepr.2025.101554","DOIUrl":"10.1016/j.jhepr.2025.101554","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101554"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266656","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":"The efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma in relation to tumor-infiltrating lymphocytes","authors":"Hiroaki Kanzaki ,&nbsp;Takamasa Ishino ,&nbsp;Sadahisa Ogasawara ,&nbsp;Takahiro Tsuchiya ,&nbsp;Makoto Fujiya ,&nbsp;Midori Sawada ,&nbsp;Ryo Izai ,&nbsp;Teppei Akatsuka ,&nbsp;Chihiro Miwa ,&nbsp;Takuya Yonemoto ,&nbsp;Sae Yumita ,&nbsp;Miyuki Nakagawa ,&nbsp;Ryuta Kojima ,&nbsp;Keisuke Koroki ,&nbsp;Masanori Inoue ,&nbsp;Kazufumi Kobayashi ,&nbsp;Naoya Kanogawa ,&nbsp;Masato Nakamura ,&nbsp;Takayuki Kondo ,&nbsp;Shingo Nakamoto ,&nbsp;Yosuke Togashi","doi":"10.1016/j.jhepr.2025.101614","DOIUrl":"10.1016/j.jhepr.2025.101614","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Atezolizumab plus bevacizumab (Atez/Bev) improves prognosis in advanced hepatocellular carcinoma, but its mechanisms remain unclear. This study aims to identify predictive biomarkers through a comprehensive analysis of the tumor microenvironment.</div></div><div><h3>Methods</h3><div>Biopsy samples from 94 patients with advanced hepatocellular carcinoma before Atez/Bev were analyzed using immunohistochemistry, bulk RNA-sequencing, flow cytometry, and multiplexed imaging. The tumor microenvironment assessment included profiling of CD8⁺ T cells and effector regulatory T (eTreg) cells. Immune dynamics were examined across baseline, in-treatment, and progression samples from each patient.</div></div><div><h3>Results</h3><div>We found favorable progression-free survival to be associated with a high percentage of programmed death-1 (PD-1) positivity in CD8⁺ T cells but not with CD8⁺ T-cell density. PD-1 positivity in CD8⁺ T cells was dichotomized at the median (58%). Building upon PD-1 positivity in CD8⁺ T cells, predominant and diffuse infiltration of CD8⁺ T cells within the tumor parenchyma was shown to be associated with improved treatment response. PD-1 positivity in eTreg cells was not associated with prognosis. Finally, we found that Bev, an antivascular endothelial growth factor antibody, suppresses the eTreg-cell activation induced by programmed death-ligand 1 (PD-L1) blockade.</div></div><div><h3>Conclusions</h3><div>We demonstrate that immunohistochemistry analysis to determine the localization and distribution of CD8⁺ T cells within the tumor is a viable means of predicting treatment efficacy for Atez/Bev and provides a valuable framework for future trial design. This is an exploratory analysis with no current consequences in clinical practice. Future studies should confirm the results in an external cohort.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that the localization and distribution pattern of CD8⁺ T cells within the tumor parenchyma are predictors of atezolizumab plus bevacizumab treatment outcomes in advanced hepatocellular carcinoma. The study further reveals that bevacizumab counteracts the potentially unfavorable influence of programmed death-ligand 1 blockade by suppressing effector regulatory T-cell activation. These findings provide both a valuable guide for determining treatment strategies in routine clinical practice and a foundation for future immunotherapy development for the treatment of advanced hepatocellular carcinoma.</div></div><div><h3>Clinical trials registration</h3><div>The study protocol was registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) (UMIN000047701).</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101614"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569495","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":"Corrigendum to “Auto-antibodies against interferons are common in people living with chronic hepatitis B virus infection and associate with PegIFNα non-response” [J Hepatol (2025) 101382]","authors":"Douglas L. Fink ,&nbsp;David Etoori ,&nbsp;Robert Hill ,&nbsp;Orest Idilli ,&nbsp;Nikita Kartikapallil ,&nbsp;Olivia Payne ,&nbsp;Sarah Griffith ,&nbsp;Hannah F. Bradford ,&nbsp;Claudia Mauri ,&nbsp;Patrick T.F. Kennedy ,&nbsp;Laura E. McCoy ,&nbsp;Mala K. Maini ,&nbsp;Upkar S. Gill","doi":"10.1016/j.jhepr.2025.101520","DOIUrl":"10.1016/j.jhepr.2025.101520","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101520"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266658","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":"Corrigendum to “Missed opportunities in HCV care: Trends in late diagnosis and treatment” [JHEP Reports 7 (2025) 101474]","authors":"Shane Tillakeratne ,&nbsp;Heather Valerio ,&nbsp;Maryam Alavi ,&nbsp;Behzad Hajarizadeh ,&nbsp;Marianne Martinello ,&nbsp;Kathy Petoumenos ,&nbsp;Jacob George ,&nbsp;Janaki Amin ,&nbsp;Gail V. Matthews ,&nbsp;Jason Grebely ,&nbsp;Sallie-Anne Pearson ,&nbsp;Gregory J. Dore","doi":"10.1016/j.jhepr.2025.101561","DOIUrl":"10.1016/j.jhepr.2025.101561","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101561"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266651","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":"Editorial Board page","authors":"","doi":"10.1016/S2589-5559(25)00289-7","DOIUrl":"10.1016/S2589-5559(25)00289-7","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101607"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266653","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":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(25)00291-5","DOIUrl":"10.1016/S2589-5559(25)00291-5","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101609"},"PeriodicalIF":7.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266657","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}