JHEP Reports最新文献

{"title":"Conjugated bile acid-driven CD14+CD16+ monocyte infiltration promotes cholestatic liver injury by enhancing hepatocyte necroptosis","authors":"Zhixian Zhu ,&nbsp;Ziqian Xu ,&nbsp;Xinyu Cao ,&nbsp;Nan Zhao ,&nbsp;Jiaxin Lei ,&nbsp;Ling Li ,&nbsp;Xi Li ,&nbsp;Yan Li ,&nbsp;Mingqiao Li ,&nbsp;Tian Ren ,&nbsp;Li Liu ,&nbsp;James L. Boyer ,&nbsp;Shi-ying Cai ,&nbsp;Qiong Pan ,&nbsp;Xiaoxun Zhang ,&nbsp;Jin Chai","doi":"10.1016/j.jhepr.2025.101517","DOIUrl":"10.1016/j.jhepr.2025.101517","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cell death and inflammation cause liver injury during cholestasis. Monocyte infiltration is crucial for the inflammatory response in tissues and organs. Thus, to study the role of monocytes in cholestatic liver disease, we used single-cell RNA sequencing (scRNA-seq) to analyze liver non-parenchymal cells (NPCs) from patients with obstructive cholestasis (OC).</div></div><div><h3>Methods</h3><div>Hepatic monocyte infiltration in liver was assessed using scRNA-seq and multiplex immunofluorescence. <em>In vivo</em> functional validation was conducted through serum biochemistry, liver histopathology, RT-qPCR, and Western blotting after intermediate monocyte infusion and elimination in mice. <em>In vitro</em>, CD14⁺CD16⁺ monocytes were isolated by flow cytometry for analysis of tumor necrosis factor-alpha (TNFα) and factor-related apoptosis ligand (FASL) expression.</div></div><div><h3>Results</h3><div>scRNA-seq and multiplex immunofluorescence revealed that CD14⁺CD16⁺ monocyte infiltration was increased in OC livers (n = 5–20; <em>p</em> &lt;0.0001). The number of CD14⁺CD16⁺ monocytes was positively correlated with liver injury severity (alanine aminotransferase (ALT), n = 20, <em>p</em> = 0.00002; aspartate aminotransferase (AST), n = 20, <em>p</em> = 0.002). Infusion of human CD14⁺CD16⁺ monocytes (<em>i.e.</em> human intermediate monocytes) exacerbated cholestatic liver injury in mice fed 1% lithocholic acid (ALT, n = 5, <em>p</em> &lt;0.01; AST, n = 5, <em>p</em> &lt;0.01). Meanwhile, mice that received mouse intermediate monocytes also exhibited higher cholestatic liver injury (ALT, n = 5, <em>p</em> &lt;0.01; AST, n = 5, <em>p</em> &lt;0.01). Mechanistically, CD14⁺CD16⁺ monocyte infiltration increased hepatic levels of TNFα (n = 5, <em>p</em> &lt;0.01) and FASL (n = 5, <em>p</em> &lt;0.01), activating the receptor-interacting serine/threonine-protein kinase (RIPK)-1–RIPK3–mixed-lineage kinase domain-like protein (MLKL) axis to promote hepatocyte necroptosis. CD14⁺CD16⁺ monocytes isolated from peripheral blood mononuclear cells (PBMCs) from patients with OC expressed higher levels of TNFα (n = 3, <em>p</em> &lt;0.05) and FASL (n = 3, <em>p</em> &lt;0.05) compared with other PBMC populations. Bile acid-stressed hepatocytes drove CD14⁺CD16⁺ monocyte infiltration via JNK/c-Jun-mediated CCL2 (n = 5-20, <em>p</em> &lt;0.0001) and CCL3 (n = 5-20, <em>p</em> &lt;0.05) upregulation.</div></div><div><h3>Conclusion</h3><div>Infiltrated CD14⁺CD16⁺ monocytes promote hepatocyte necroptosis and exacerbate cholestatic liver injury. Thus, targeting their chemotaxis represents a promising therapeutic strategy against cholestasis.</div></div><div><h3>Impact and implications</h3><div>This study revealed that CD14⁺CD16⁺ monocyte-der","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101517"},"PeriodicalIF":7.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019813","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":"Randomized phase II study comparing two doses of regorafenib in second-line treatment for advanced hepatocellular carcinoma","authors":"Keisuke Koroki ,&nbsp;Sadahisa Ogasawara ,&nbsp;Sae Yumita ,&nbsp;Miyuki Nakagawa ,&nbsp;Hiroaki Kanzaki ,&nbsp;Kazufumi Kobayashi ,&nbsp;Masanori Inoue ,&nbsp;Masato Nakamura ,&nbsp;Naoya Kanogawa ,&nbsp;Takayuki Kondo ,&nbsp;Eiichiro Suzuki ,&nbsp;Yoshihiko Ooka ,&nbsp;Shingo Nakamoto ,&nbsp;Yuki Shiko ,&nbsp;Yoshihito Ozawa ,&nbsp;Yosuke Inaba","doi":"10.1016/j.jhepr.2025.101509","DOIUrl":"10.1016/j.jhepr.2025.101509","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;The RESORCE trial confirmed regorafenib as a second-line treatment for advanced hepatocellular carcinoma (HCC) in patients who tolerated sorafenib. However, its safety and efficacy in patients with diverse treatment histories remain unknown. The REGAIN study sought to assess regorafenib in patients not included in the RESORCE trial.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This single-center, randomized, open-label, dose-comparison trial included patients with HCC who had previously received sorafenib 200 mg/day or 400 mg every other day (Arm A), lenvatinib (Arm B), or atezolizumab plus bevacizumab (Arm C). Patients were randomly assigned to receive regorafenib at the standard (160 mg/day) or reduced (80 mg/day) starting dose. For early safety assessment, discontinuation as the result of adverse events (AEs) during the first cycle among the first six patients in each dose group was defined as a measure of evaluation. The primary endpoint was time to progression (TTP), and efficacy was evaluated using mRECIST.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Thirty-six patients were enrolled (12 per arm). Although the study did not reach its originally planned sample size, it provided safety and exploratory efficacy data. Discontinuation in the first cycle as a result of AEs was observed in one patient (Arm C, standard-dose group). The efficacy outcomes were comparable between the standard- and reduced-dose groups: median TTP was 4.6 &lt;em&gt;vs.&lt;/em&gt; 3.0 months (&lt;em&gt;p&lt;/em&gt; = 0.810), progression-free survival was 4.6 &lt;em&gt;vs.&lt;/em&gt; 3.4 months (&lt;em&gt;p&lt;/em&gt; = 0.811), and overall survival was 18.1 &lt;em&gt;vs.&lt;/em&gt; 17.7 months (&lt;em&gt;p&lt;/em&gt; = 0.728). The objective response rate was 22.2% in both groups.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Regorafenib can be safely administered with varying treatment histories. Further investigation is warranted to validate the clinical utility of reduced starting dose, which may optimize treatment strategies for advanced HCC in real-world settings.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Sequencing and extending systemic therapies can improve the prognosis of advanced hepatocellular carcinoma (HCC), but comprehensive evidence on second-line and subsequent treatments remains limited. This study evaluated regorafenib in modern clinical scenarios, including patients intolerant to sorafenib and those previously treated with lenvatinib or atezolizumab plus bevacizumab. Regorafenib was safely administered at 160 mg/day and 80 mg/day, and an exploratory efficacy analysis found no significant difference between the two starting doses. These findings support the integration of regorafenib into personalized treatment strategies for advanced HCC, providing physicians specializing in liver cancer treatment with greater flexibility in selecting appropriate therapeutic sequences while also expanding treatment options for patients facing increasingly limited systemic therapy choices.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;C","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101509"},"PeriodicalIF":7.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096422","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":"Tumor necrosis facilitates perihilar cholangiocarcinoma metastasis by ANGPTL6-augmented vessel permeability and tumor dissemination","authors":"Honghua Zhang ,&nbsp;Wendong Chen ,&nbsp;Xiuxian Li ,&nbsp;Zhixiao Song ,&nbsp;Yang Liu ,&nbsp;Shaoru Liu ,&nbsp;Zhiyang Su ,&nbsp;Wenrui Wu ,&nbsp;Huiying Chen ,&nbsp;Chao Qin ,&nbsp;Shusheng Lin ,&nbsp;Fapeng Zhang ,&nbsp;Xinjun Lu ,&nbsp;Qibin Tang ,&nbsp;Xianhuan Yu ,&nbsp;Leibo Xu ,&nbsp;Chao Liu","doi":"10.1016/j.jhepr.2025.101514","DOIUrl":"10.1016/j.jhepr.2025.101514","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Tumor necrosis is a pathological feature of solid tumors that is associated with poor prognosis and aggressive characteristics. However, its prognostic significance and underlying mechanisms in perihilar cholangiocarcinoma (pCCA) remain unclear. This study aimed to investigate the prognostic impact, clinic-pathological relevance, molecular regulation, and microenvironment alterations associated with tumor necrosis in pCCA.</div></div><div><h3>Methods</h3><div>We recruited 306 eligible patients with pCCA to assess the prognostic impact and clinic-pathological relevance of pathological tumor necrosis. Laser capture microdissection coupled with high-resolution mass spectrometry was used to identify the molecular changes in pCCA cells within peri-necrotic regions. Single-cell RNA sequencing was performed to elucidate the microenvironment alterations associated with tumor necrosis.</div></div><div><h3>Results</h3><div>Tumor necrosis was present in 52.9% (162/306) of patients with pCCA and was identified as an independent risk factor associated with adverse prognosis (hazard ratio 1.42, 95% CI 1.02–1.97, <em>p</em> = 0.039), tumor dissemination, cancer embolus, and aggressive progression. Spatial proteomics identified angiopoietin-like 6 (ANGPTL6) as a tumor-specific protein enriched in pCCA cells in peri-necrotic regions. <em>In vitro</em> and <em>in vivo</em> studies demonstrated that ANGPTL6 promoted pCCA progression by increasing vessel permeability, leading to tumor dissemination, increased metastatic burden, and poorer prognosis. Furthermore, pathological tumor necrosis was found to be associated with an immunosuppressive microenvironment in pCCA tumors.</div></div><div><h3>Conclusions</h3><div>Pathological tumor necrosis leads to augmented vessel permeability and tumor dissemination in pCCA. ANGPTL6 is a potential target for mitigating the metastatic burden in pCCA.</div></div><div><h3>Impact and implications</h3><div>Pathological tumor necrosis has been identified as an independent risk factor in perihilar cholangiocarcinoma (pCCA), showing positive correlation with metastatic burden. Spatial proteomics and <em>in vitro</em>/<em>in vivo</em> experiments elucidated the detrimental effects of angiopoietin-like 6 (ANGPTL6) in necrotic tumors through augmenting vessel permeability for tumor dissemination. A transition toward an immunosuppressive microenvironment was revealed in pCCA tumors with pathological tumor necrosis. Our findings provide a rationale for mitigating the metastatic burden in pCCA.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101514"},"PeriodicalIF":7.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019815","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":"Landscape of T-cell exhaustion heterogeneity and HBV integration in virus-related HCC revealed by whole-exome, transcriptome, and single-cell sequencing","authors":"Soon Kyu Lee ,&nbsp;Jinyeong Lim ,&nbsp;Joo Yeon Jhun ,&nbsp;Jeonghyeon Moon ,&nbsp;Hye Seon Kim ,&nbsp;Jong Young Choi ,&nbsp;Ho Joong Choi ,&nbsp;Young Kyoung You ,&nbsp;Ji Won Han ,&nbsp;Pil Soo Sung ,&nbsp;Kwon Yong Tak ,&nbsp;Seung Kew Yoon ,&nbsp;Woong-Yang Park ,&nbsp;Mi-La Cho ,&nbsp;Jeong Won Jang","doi":"10.1016/j.jhepr.2025.101518","DOIUrl":"10.1016/j.jhepr.2025.101518","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>To enhance our understanding of the tumor immune microenvironment (TIME) in hepatocellular carcinoma (HCC), we investigated the heterogeneity of T-cell exhaustion and its association with HBV integrations and direct oncogenic potential in HCC.</div></div><div><h3>Methods</h3><div>We conducted a multi-omics analysis, including single-cell RNA sequencing, whole-exome sequencing, whole-transcriptome sequencing, and next-generation sequencing (NGS)-based HBV integration analysis, in eight patients with virus-related HCC. For validation, bulk RNA sequencing and NGS-based HBV integration analysis were performed in an independent cohort (n = 106).</div></div><div><h3>Results</h3><div>Based on the expression scores of exhaustion markers in effector CD8⁺ T cells, patients were classified into high (n = 2) and low (n = 6) exhaustion groups (<em>p</em> &lt;0.001). The high-exhaustion group exhibited higher clonal expansion (Gini index: 0.83 <em>vs.</em> 0.48, <em>p</em> = 0.006) and sharing of CD8⁺ T effector memory and cycling T cells with elevated exhaustion markers. This group also showed increased clonal expansion of CD4⁺ regulatory T cells and follicular helper T cells (<em>p</em> &lt;0.001) with higher PDCD1 expression. In addition, the high-exhaustion group had higher <em>TP53</em> mutation rates and signature scores for proliferation subtypes compared with the low-exhaustion group, who predominantly harbored <em>TERT</em> mutations. Moreover, the high-exhaustion group demonstrated more pronounced HBV integrations with elevated intrahepatic covalently closed circular DNA (cccDNA) and pregenomic (pg)RNA levels. Similarly, in the validation cohort, the high-exhaustion group (n = 28) demonstrated stronger proliferation subtype signatures (<em>p</em> &lt;0.001), along with higher HBV integrations, S-fusion transcripts, and an increased intrahepatic viral reservoir (cccDNA/pgRNA) (<em>p</em> &lt;0.05) compared with the low-exhaustion group (n = 78).</div></div><div><h3>Conclusions</h3><div>Our study revealed the heterogeneity in T-cell exhaustion in the TIME of HCC, along with differences in HBV integrations and molecular subtypes. These findings provide insight into the intricate relationship between high exhaustion, proliferation subtype, increased HBV integrations, and enhanced HBV-induced oncogenic potential in virus-related HCC.</div></div><div><h3>Impact and implications</h3><div>This study provides a comprehensive immune landscape of T-cell exhaustion using multi-omics analysis, offering critical insights into T cell heterogeneity in virus-related HCC. It establishes a strong association between higher HBV integration, enhanced oncogenic potential, T-cell exhaustion, and proliferation subtypes in HCC. Our results also establish a basis for personalized therapies tailored to the immune-exhaustion status within the TIME of each patient with HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 11","pages":"Article 101518"},"PeriodicalIF":7.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145218881","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":"Peginterferon-alpha-2a add-on to treatment with siRNA JNJ-73763989 in virologically suppressed chronic hepatitis B: The phase II PENGUIN study","authors":"Edward Gane ,&nbsp;Ewa Janczewska ,&nbsp;Tetsuo Takehara ,&nbsp;Wan-Long Chuang ,&nbsp;Cheng-Yuan Peng ,&nbsp;Maria Hlebowicz ,&nbsp;Yasuhiro Asahina ,&nbsp;Ting-Tsung Chang ,&nbsp;Ronald Kalmeijer ,&nbsp;John Jezorwski ,&nbsp;Gloria Kim ,&nbsp;Zacharias Anastasiou ,&nbsp;Thomas N. Kakuda ,&nbsp;Thierry Verbinnen ,&nbsp;Nonko Pehlivanov ,&nbsp;Adam Bakala ,&nbsp;Oliver Lenz ,&nbsp;Michael Biermer","doi":"10.1016/j.jhepr.2025.101516","DOIUrl":"10.1016/j.jhepr.2025.101516","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Previous studies showed that combination treatment with short interfering RNA JNJ-73763989 (JNJ-3989) ± capsid assembly modulator bersacapavir (JNJ-56136379) and nucleos(t)ide analogs (NAs) was well tolerated by patients with chronic HBV (CHB), with JNJ-3989 dose-dependent reductions in viral markers, including HBsAg. The open-label, single-arm phase IIa PENGUIN study (NCT04667104) evaluated this regimen plus pegylated interferon alpha-2a (PegIFN-α2a) in patients with virologically suppressed CHB.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Patients who were either HBeAg-positive or -negative virologically suppressed and taking NAs were included; all received JNJ-3989 ± bersacapavir for 24 weeks (some either did not start or discontinued bersacapavir as a result of protocol amendment) with PegIFN-α2a added during the final 12 weeks of treatment. The primary endpoint was the proportion of patients with ≥2 log&lt;sub&gt;10&lt;/sub&gt; IU/ml HBsAg reduction from baseline at week 24 (W24). Safety, tolerability, and proportion of patients meeting predefined NA stopping criteria were assessed. After 24 weeks of treatment, NA was stopped when stopping criteria were met; all patients were followed for 48 weeks. Efficacy and safety endpoints were summarized using descriptive statistics.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In total, 48 patients (HBeAg positive, n = 11; HBeAg negative, n = 37) were enrolled; 47 reached follow-up week 48 (FUW48). Of the 48 patients, 31 (64.6%) achieved the primary endpoint; one achieved HBsAg seroclearance (&lt;0.05 IU/ml) at both W24 and FUW48 after stopping NA. Mean HBsAg changes from baseline were -1.43, -2.18, and -0.71 log&lt;sub&gt;10&lt;/sub&gt;IU/ml at W12, W24, and FUW48, respectively. At W24, 15/48 (31.3%) patients met NA stopping criteria; 11/15 (73.3%) remained off NA by FUW48. One patient achieved functional cure at FUW48. Adverse events were consistent with known PegIFN-α2a safety profiles.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Treatment with JNJ-3989 ± bersacapavir + NA and PegIFN-α2a was generally well tolerated. Most patients had pronounced HBsAg reductions from baseline, no additional benefit from PegIFN-α2a, and did not achieve functional cure.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Clinical Trials registration&lt;/h3&gt;&lt;div&gt;The study is registered at &lt;span&gt;&lt;span&gt;ClinicalTrials.gov&lt;/span&gt;&lt;svg&gt;&lt;path&gt;&lt;/path&gt;&lt;/svg&gt;&lt;/span&gt; (NCT04667104).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Previous studies with JNJ-73763989 (JNJ-3989) ± bersacapavir (JNJ-56136379) and nucleos(t)ide analogs (NAs) in patients with chronic hepatitis B (CHB) have demonstrated JNJ-3989 dose-dependent and robust reductions in viral markers; however, functional cure was only rarely achieved. The current study assessed whether the addition of pegylated interferon alpha-2a (PegIFN-α2a) to a JNJ-3989-based regimen after HBsAg levels were reduced would lead to further HBsAg declines and improved outcomes during off-treatment follow-up. Study result","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101516"},"PeriodicalIF":7.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902584","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":"Elevated FBXO45 promotes TFG ubiquitination and drives lung metastasis of hepatocellular carcinoma","authors":"Zhen-Bao Zhu ,&nbsp;Di Wu ,&nbsp;Cui Mao ,&nbsp;Yong-Peng Gu ,&nbsp;Jie Zhang,&nbsp;Lei Fang,&nbsp;Lei-Da Zhang,&nbsp;Xiao-Tong Lin,&nbsp;Chuan-Ming Xie","doi":"10.1016/j.jhepr.2025.101519","DOIUrl":"10.1016/j.jhepr.2025.101519","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Elevated F-box/SPRY domain protein 1 (FBXO45) expression is associated with human hepatocellular carcinoma (HCC). While TP53 mutations represent a common genetic alteration in HCC, the potential regulatory interplay between TP53 and FBXO45 in modulating HCC progression remains unclear.</div></div><div><h3>Methods</h3><div>We analyzed the relationship between TP53 and FBXO45 in patients with HCC. A series of assays were also performed to explore the effect of FBXO45 on invasion and metastasis in TP53-mutated HCC cell lines and mouse models. These experimental findings were further validated in clinical samples.</div></div><div><h3>Results</h3><div>FBXO45 expression was upregulated in 78.3% (83/106) of patients with HCC with TP53 mutation, marking an aggressive subtype. Overexpression of FBXO45 significantly enhanced HCC cell migration and invasion capacity (<em>p</em> &lt;0.001), whereas FBXO45 silencing suppressed these effects (<em>p</em> &lt;0.01). Mechanistically, FBXO45 promoted Trk-fused gene (TFG) Lys103 ubiquitination and then increased its stability. This post-translational modification facilitates the binding of transcription factor activating transcription factor 2 (ATF2), leading to subsequent upregulation of nuclear factor-kappa B (NF-κB) p65 expression and ultimately promoting the migratory and invasive properties of TP53-mutant HCC cells. <em>In vivo</em> validation using an orthotopic xenograft model showed that FBXO45 overexpression significantly promoted HCC lung metastasis incidence (7/9 mice with metastases), whereas TFG knockdown abrogated this metastatic potential. Clinically, patients exhibiting high co-expression of FBXO45 and TFG defined an aggressive HCC subtype with significantly worse prognosis (<em>p =</em> 0.0015).</div></div><div><h3>Conclusions</h3><div>Our results provide new mechanistic insight into the role of FBXO45 in driving HCC invasion and metastasis. Therefore, targeting the TP53–FBXO45–TFG–ATF2–NF-κB axis represents a promising therapeutic approach for treating aggressive HCC with TP53 mutations.</div></div><div><h3>Impact and implications</h3><div>This study highlights that FBXO45 is highly expressed in patients with HCC with TP53 mutations. FBXO45 promotes HCC lung metastasis by activating the TFG–ATF2–NF-κB–epithelial–mesenchymal transition signaling axis. In addition, we found that targeting the TP53–FBXO45–TFG–ATF2–NF-κB axis could be a novel approach for the treatment of metastatic HCC.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101519"},"PeriodicalIF":7.5,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096423","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":"Cystic fibrosis liver disease progression in the era of elexacaftor–tezacaftor–ivacaftor","authors":"Charlotte Mouliade ,&nbsp;Lucia Parlati ,&nbsp;Stylianos Tzedakis ,&nbsp;Mathis Collier ,&nbsp;Samir Bouam ,&nbsp;Anais Vallet-Pichard ,&nbsp;Valérie D’Halluin-Venier ,&nbsp;Reem Kanaan ,&nbsp;Stanislas Pol ,&nbsp;Philippe Sogni ,&nbsp;Pierre-Régis Burgel ,&nbsp;Vincent Mallet ,&nbsp;for the Demosthenes Research Group","doi":"10.1016/j.jhepr.2025.101512","DOIUrl":"10.1016/j.jhepr.2025.101512","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The effect of elexacaftor–tezacaftor–ivacaftor (ETI) on cystic fibrosis liver disease (CFLD) outcomes remains unknown. Thus, we investigated the association between the ETI rollout and trends in CFLD progression in a nationwide cohort.</div></div><div><h3>Methods</h3><div>Using the French National Hospital Discharge Database (2014–2023), we measured the incidence of CFLD progression (decompensated cirrhosis, gastroesophageal variceal bleeding, primary liver cancer, or liver transplantation) before and after ETI became available (December 2019) in patients with cystic fibrosis (pwCF) aged ≥12 years. Death without CFLD progression and lung transplantation were treated as competing events. Incidence rates were compared across ETI calendar eras in both the full cohort and a 1:1 propensity score-matched sample. Analyses used Kaplan–Meier curves, Fine–Gray competing risk models, and adjusted incidence rate ratios (aIRRs).</div></div><div><h3>Results</h3><div>The cohort included 10,083 pwCF (median age: 19 years [IQR 14–29]; 52.6% male), with 24.6% censored pre-ETI and 75.4% post-ETI. The overall incidence of CFLD progression was 3.7 per 1,000 person-years: 25.4 pre-ETI versus 1.2 post-ETI (<em>p</em> &lt;0.001). The incidence of all CFLD outcomes, including non-bleeding varices, declined post-ETI (<em>p</em> &lt;0.001). In matched analyses, pwCF censored during the ETI era had a lower incidence of CFLD progression (aIRR 0.28, 95% CI: 0.18–0.43; <em>p</em> &lt;0.001). In addition, deaths in pwCF occurred at an older age during the ETI era.</div></div><div><h3>Conclusions</h3><div>The incidence of CFLD progression declined during the ETI rollout. While these findings suggest an association between ETI availability and improved liver outcomes, unmeasured confounders and concurrent changes in management might have also contributed. Thus, further studies are needed to confirm causality and understand underlying mechanisms.</div></div><div><h3>Impact and implications</h3><div>In this nationwide French cohort study of over 10,000 people with cystic fibrosis, we observed a significant decline in the incidence of cystic fibrosis liver disease outcomes following the rollout of elexacaftor–tezacaftor–ivacaftor (ETI) in December 2019. The rate dropped from 25.4 to 1.2 per 1,000 person-years post-ETI. Matched analyses confirmed a reduced risk of liver disease progression, with an adjusted incidence rate ratio of 0.28. Although the findings suggest ETI may improve liver outcomes in people with cystic fibrosis, potential confounding factors necessitate further research to establish causality and understand the underlying biological mechanisms.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101512"},"PeriodicalIF":7.5,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155328","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":"Impact of tenofovir vs. entecavir treatment on progression of chronic hepatitis B: A nationwide cohort study","authors":"Wan-Jung Wu ,&nbsp;Wen-Jie Liu ,&nbsp;Chih-Lin Lin ,&nbsp;Chun-Jen Liu ,&nbsp;Yi-Wen Huang ,&nbsp;Jui-Ting Hu ,&nbsp;Ming-Whei Yu","doi":"10.1016/j.jhepr.2025.101511","DOIUrl":"10.1016/j.jhepr.2025.101511","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Conflicting evidence exists on hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB) receiving tenofovir &lt;em&gt;vs.&lt;/em&gt; entecavir. We assessed the impacts of the two drugs on the clinical trajectory of CHB at a population level.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a retrospective nationwide cohort study using data from Taiwan’s National Health Insurance Research Database, including 55,885 patients with CHB who were treatment-naïve aged 30–75 years receiving tenofovir (n = 17,137) or entecavir (n = 38,748) monotherapy for ≥3 months between November 2009 and December 2020, and followed until December 2022. Multi-state modeling was applied to evaluate treatment impacts on disease progression trajectory, comprising CHB (with/without compensated cirrhosis), hepatic decompensation, HCC, death, and a switching treatment state. Propensity score matching/weighting and subgroup analyses were used to confirm the robustness of findings.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;During a median 6.3 years of follow-up, 1,524 patients developed hepatic decompensation, 3,591 developed HCC, and 3,436 died. Tenofovir compared with entecavir was associated with lower risk of CHB progression, with adjusted-hazard ratios (95% CIs) of 0.84 (0.75–0.95) and 0.76 (0.70–0.83), respectively, for transitions to hepatic decompensation and HCC from baseline, and 0.65 (0.48–0.89) for HCC risk from decompensation. Propensity score matching/weighting analyses yielded similar results. Among patients without experiencing decompensation, a significantly lower HCC risk with tenofovir was observed across multiple subgroups, including age, sex, diabetes, and cirrhosis, and by sensitivity analyses. The 5-year risk of major adverse liver-related outcomes (decompensation, HCC, and liver-related deaths) was 5.5% and 7.5% for tenofovir and entecavir, respectively (adjusted-hazard ratio 0.80; 95% CI 0.74–0.85).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Using multi-state modeling on the temporal evolution of CHB severity, long-term tenofovir treatment compared with entecavir was associated with a lower risk of severe liver outcomes.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;The comparative effectiveness of tenofovir &lt;em&gt;vs.&lt;/em&gt; entecavir treatment in preventing hepatocellular carcinoma (HCC) for patients with chronic hepatitis B (CHB) remains controversial. Using a nationwide cohort study involving 55,885 patients to investigate CHB as a multi-state disease over 13 years, we show that tenofovir (&lt;em&gt;vs.&lt;/em&gt; entecavir) treatment is associated with lower risks of HCC, hepatic decompensation, and a composite endpoint of adverse liver-related outcomes (hepatic decompensation, HCC, and liver-related deaths), regardless of age, sex, diabetes, alcohol-related disorders, and cirrhosis state. Our results provide new evidence justifying the use of tenofovir or entecavir to prevent the evolution of CHB severity.&lt;/div&gt;&lt;/","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101511"},"PeriodicalIF":7.5,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902508","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":"Improving risk stratification and detection of early HCC using ultrasound-based deep learning models","authors":"Jérémy Dana ,&nbsp;Adrien Meyer ,&nbsp;Anita Paisant ,&nbsp;Agnès Rode ,&nbsp;Riccardo Sartoris ,&nbsp;Olivier Séror ,&nbsp;Christophe Cassinotto ,&nbsp;Laurent Milot ,&nbsp;Jules Grégory ,&nbsp;Jules Cœur ,&nbsp;Jérôme Lebigot ,&nbsp;Valentina Schembri ,&nbsp;François Villeret ,&nbsp;Armelle-Natsuo Takeda ,&nbsp;Maxime Ronot ,&nbsp;Valérie Vilgrain ,&nbsp;Thomas F. Baumert ,&nbsp;Benoit Gallix ,&nbsp;Nicolas Padoy ,&nbsp;Pierre Nahon","doi":"10.1016/j.jhepr.2025.101510","DOIUrl":"10.1016/j.jhepr.2025.101510","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Hepatocellular carcinoma (HCC) surveillance programs are suboptimal. We aimed to design an ultrasound-based deep learning model for HCC risk stratification (STARHE-RISK) and early-stage HCC detection (STARHE-DETECT) in patients with compensated advanced chronic liver disease (cACLD).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;This prospective multicentric study included 403 adult patients with cACLD of all causes enrolled in a surveillance program for at least 6 months without prior history of HCC. STARHE-RISK was trained on ultrasound cine clips of the non-tumoral liver parenchyma using two classes: cases (n = 152 patients with early-stage HCC; 137/152 [82%] male; median age 63 years) and controls (n = 170 patients without HCC at inclusion and during a subsequent 1-year follow-up; 120/170 [71%] male; median age 69 years). STARHE-DETECT was trained on tumour ultrasound cine clips. The training/validation and testing sets were stratified according to potential confounders, and 50 patients who were balanced in both groups were allocated to the independent testing set based on sample size calculation. Statistical analysis included classification and detection metrics.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;STARHE-RISK achieved good prediction performances in the testing set with a 0.72 accuracy (95% CI 0.57–0.84) and an odds ratio of 6.6 (95% CI 1.9–22.7; &lt;em&gt;p&lt;/em&gt; = 0.003). The combination of STARHE-RISK and the FASTRAK score, a multi-aetiology HCC risk stratification score, achieved a higher specificity (0.86 [95% CI 0.65–0.97]) and odds ratio (8.9 [95% CI 2.1–38.3; &lt;em&gt;p&lt;/em&gt; = 0.004]) for predicting a patient at high risk of HCC development. STARHE-DETECT achieved a 0.67 mAP10, a 0.68 sensitivity (95% CI 0.47–0.85), and a 0.82 specificity (95% CI 0.69–0.91) for detecting early-stage HCC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;STARHE-RISK and STARHE-DETECT achieved robust performances for HCC risk stratification and early-stage HCC detection, respectively. They could become valuable surveillance tools and pave the way for a risk-based personalised surveillance program.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;STARHE-RISK is a reliable ultrasound-based deep learning model for hepatocellular carcinoma (HCC) risk stratification in patients with compensated advanced chronic liver disease and can be associated with complementary scores integrating clinical and blood parameters. STARHE-DETECT could become a complementary tool to visual assessment for radiologists and sonographers in HCC surveillance. Both models are based on simple and easy-to-perform ultrasound cine clip acquisitions. This study paves the way for a risk-based personalised surveillance program that will not ultimately rely on a single test but rather on a combination of approaches mixing clinical, biological, and radiological data.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Clinical Trials Registration&lt;/h3&gt;&lt;div&gt;The study is registered at &lt;span&gt;&lt;span&gt;ClinicalTria","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 10","pages":"Article 101510"},"PeriodicalIF":7.5,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019874","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":"Hepatitis D epidemiology and access to diagnostic testing among healthcare providers in Africa: A multi-country survey.","authors":"Maria Buti, C Wendy Spearman, Karin Siebelt, Manal El-Sayed","doi":"10.1016/j.jhepr.2025.101495","DOIUrl":"10.1016/j.jhepr.2025.101495","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Reliable data on the prevalence of chronic HDV infection in Africa are limited. To address this, a multi-country survey was conducted across Africa to assess healthcare providers' knowledge of HDV prevalence and the availability of diagnostic testing. This was complemented by a literature review of regional HDV prevalence data.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A 12-item web-based questionnaire, created using Google forms, was distributed to all members of SOLDA (the Society on Liver Disease in Africa) and Project ECHO Viral Hepatitis in sub-Saharan Africa (n = 1,210) through African network channels. Survey responses were analyzed using descriptive statistics; all analyses were performed using GraphPad Prism 6.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A total of 1,210 surveys were distributed and completed by 608 participants across 43/54 (80%) African countries (44% Eastern, 36% Western, 8% Southern, 6% Northern, and 6% Central regions). Participants from 24/43 (56%) countries were aware of national HDV epidemiological data, mainly in relation to HBsAg carriers (77%), blood donors (23%), patients with chronic liver disease (25%), and those with hepatocellular carcinoma (18%). Anti-HDV antibody testing was available in 30/43 (69%) countries, primarily in clinical studies. The literature review identified 49 studies from 21 countries (mainly in Western and Central Africa), revealing a particularly high HDV prevalence in some countries (Cameroon, Gabon, and Nigeria). In 16 of 22 countries, survey participants' awareness of HDV prevalence was consistent with published data.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Healthcare providers' knowledge of HDV prevalence varies across African countries, with 56% aware of national data and 73% aligned with published estimates. While diagnostic testing is available in 69% of countries, it remains limited, is seldom reimbursed, and is not routinely integrated into clinical practice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;This study provides the first continent-wide assessment of healthcare providers' knowledge of HDV prevalence and diagnostic capacity across Africa. The findings reveal significant knowledge gaps - with nearly half of respondents unaware of national HDV data, particularly in Northern Africa - and limited availability of diagnostic testing in clinical practice. While anti-HDV testing is available in 69% of surveyed countries, it is often restricted to research settings, not reimbursed, and rarely integrated into routine care. A complementary literature review confirms that most published data originate from Western and Central Africa, with particularly high HDV prevalence reported in countries such as Cameroon, Gabon, and Nigeria. The study underscores the urgent need for improved HDV surveillance, provider education, and access to diagnostics. Strengthening these areas is essential to inform national hepatitis strategies, guide targeted interventions, and suppor","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 9","pages":"101495"},"PeriodicalIF":7.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}