Journal of Clinical and Translational Hepatology最新文献

{"title":"Antimitochondrial Antibody Measurements in the Diagnosis of Antimitochondrial Antibody-negative and Alkaline Phosphatase-positive Primary Biliary Cholangitis: An Update and Review.","authors":"Karol Suchowiecki, George Y Wu","doi":"10.14218/JCTH.2026.00117","DOIUrl":"10.14218/JCTH.2026.00117","url":null,"abstract":"<p><p>Antimitochondrial antibody (AMA)-negative primary biliary cholangitis (PBC) is a rare presentation of PBC that comprises 5%-10% of all PBC patients. The pathogenesis of AMA-negative PBC appears to be similar to that of AMA-positive PBC. AMA-negative PBC presents similarly to AMA-positive PBC, with symptoms of cholestasis, fatigue, and pruritus most commonly reported. Defective bicarbonate production, resulting in acidification of bile and bile acids, has been proposed as the primary mechanism of damage to bile ducts and hepatocytes and is reflected in elevations of alkaline phosphatase and aminotransferases. Chronic damage can lead to the development of cirrhosis. The diagnosis is made by the finding of AMA negativity by ELISA or assays of similar sensitivity and a positive PBC-specific antinuclear antibody (ANA; anti-glycoprotein 210 and anti-speckled 100 kDa protein) test. In cases in which anti-glycoprotein 210 and anti-speckled 100 kDa protein assays are also negative, a liver biopsy is required to make the diagnosis after exclusion of other causes of cholestasis by magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography. Treatment for AMA-negative PBC is the same as for AMA-positive cases, with ursodeoxycholic acid as the first-line treatment. Current treatment is most effective in early stages, where it slows but does not eliminate progression. Risk stratification by validated tools such as the GLOBE and UK-PBC scores remains useful in AMA-negative PBC.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"665-673"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSTM3 Knockdown Promotes Liver Fibrosis Reversal by Inhibiting Hepatic Stellate Cell Activation via PPARγ Signaling.","authors":"Chenxue Hou, Bingqing Yang, Yuanying Zhao, Hao Chang, Tong Bu, Qi Wang, Yue Li","doi":"10.14218/JCTH.2025.00658","DOIUrl":"10.14218/JCTH.2025.00658","url":null,"abstract":"<p><strong>Background and aims: </strong>Liver fibrosis is a pivotal and reversible stage in the progression of chronic liver disease. However, the mechanisms underlying fibrosis reversal remain unclear, and effective diagnostic biomarkers are lacking in clinical practice. In this study, we aimed to elucidate the role and molecular mechanisms of glutathione S-transferase Mu 3 (GSTM3) in liver fibrosis reversal, and preliminarily determine whether GSTM3 can serve as a novel biomarker for liver fibrosis reversal.</p><p><strong>Methods: </strong>Carbon tetrachloride-induced mouse models of liver fibrosis and spontaneous reversal were established. Proteomic analysis was used to identify proteins shared between liver tissue and serum that were continuously downregulated during fibrosis reversal. The expression of GSTM3 was evaluated in the livers of mice undergoing fibrosis reversal and in clinical samples from patients with liver fibrosis. Hepatic stellate cells (HSCs) were transfected with <i>Gstm3</i>-silencing RNA or an overexpression plasmid to assess the effects on fibrosis markers. RNA sequencing analyses were performed, and the underlying molecular mechanisms were investigated.</p><p><strong>Results: </strong>Proteomic analysis revealed significantly decreased GSTM3 levels in both hepatic tissue and serum in mice undergoing fibrosis reversal, and its expression was negatively correlated with the extent of reversal. GSTM3 levels were markedly increased in the hepatic tissue and serum of patients with liver fibrosis. GSTM3 expression was upregulated in transforming growth factor-β-stimulated HSCs. GSTM3 knockdown inhibited the expression of fibrosis markers, such as collagen type I α1 and tissue inhibitor of metalloproteinase 1, whereas its overexpression promoted their expression. Mechanistic studies indicated that GSTM3 knockdown activated peroxisome proliferator-activated receptor γ (PPARγ) signaling and downregulated its downstream targets, cluster of differentiation 36 and fatty acid-binding protein 4, thereby suppressing HSC activation.</p><p><strong>Conclusions: </strong>GSTM3 knockdown promotes liver fibrosis reversal via PPARγ signaling-mediated inhibition of HSC activation. Therefore, GSTM3 is a promising therapeutic target and diagnostic biomarker for liver fibrosis.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"613-627"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reducing the Risk of Overt Hepatic Encephalopathy Recurrence: A Narrative Review.","authors":"Nikolaos T Pyrsopoulos, Nadege Gunn, Prasun K Jalal, George E Catinis","doi":"10.14218/JCTH.2025.00698","DOIUrl":"10.14218/JCTH.2025.00698","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) is a neurologic complication of advanced liver disease (e.g., cirrhosis) resulting in impaired functioning and reduced quality of life. This condition is associated with a substantial burden for patients and their caregivers and carries a poor prognosis and increased risk of hospitalization and mortality. This narrative review discusses the burden of HE, precipitating risk factors, and clinical considerations for reducing the risk of overt HE (OHE) recurrence in adults with cirrhosis. Key precipitating factors include certain medications, constipation, dehydration, uncontrolled diabetes mellitus, electrolyte imbalances, gastrointestinal bleeding, infection, and sarcopenia, among others. Identification and treatment of precipitating factors are critical steps in the management of HE. Components of ongoing care include patient and caregiver education, nutritional supplementation and sleep management, pharmacotherapy, and nonpharmacologic interventions (e.g., spontaneous portosystemic shunt embolization and liver transplantation in appropriate patients). Clinical guidelines recommend lactulose therapy as secondary prophylaxis after an initial episode of OHE. Rifaximin is recommended as add-on therapy to lactulose when an additional OHE episode occurs. Polyethylene glycol has been investigated as an alternative to lactulose in patients with acute HE and in those with chronic HE and a poor response to lactulose. Oral L-ornithine-L-aspartate may reduce the risk of OHE recurrence in patients with cirrhosis. Investigational agents include nitazoxanide, fecal microbiota transplantation, and the use of artificial intelligence, app-based technology, and wearable devices to facilitate acute and prophylactic management of HE.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"674-686"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-chain Fatty Acids and Bile Acids Signaling in Chronic Hepatitis B.","authors":"Siqi Sun, Sisi Yang, Yihe Yu, Jiyang Chen, Jintao Ning, Yida Yang, Hongyu Jia","doi":"10.14218/JCTH.2026.00118","DOIUrl":"10.14218/JCTH.2026.00118","url":null,"abstract":"<p><p>Chronic hepatitis B (CHB) remains a major global public health challenge. Current therapies based on nucleos(t)ide analogues and interferon mainly achieve long-term viral suppression, whereas only a small proportion of patients attain a functional cure, defined as sustained hepatitis B surface antigen loss with hepatitis B virus (HBV) DNA below the limit of quantification for at least 24 weeks after treatment discontinuation, with or without anti-HBs seroconversion. Emerging evidence from the gut-liver axis indicates that gut microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs) and bile acids (BAs), modulate the HBV life cycle and immune regulation in CHB, thereby offering therapeutic targets to overcome immune tolerance. This review summarizes the biological characteristics of SCFAs and BAs and their mechanistic roles across different stages of HBV infection, with emphasis on translational relevance. <i>In vitro</i> and animal studies suggest that butyrate and related SCFAs suppress HBV gene expression by inhibiting histone deacetylases and remodeling covalently closed circular DNA minichromatin. SCFAs may also enhance antiviral immunity, although they may reinforce immune tolerance in certain contexts. For BAs, the farnesoid X receptor, Takeda G protein-coupled receptor 5, and the HBV entry receptor sodium taurocholate cotransporting polypeptide form a key signaling hub with dual effects on viral replication and host responses. Early-phase studies suggest that farnesoid X receptor agonists, pegylated interferon-α, or nucleos(t)ide analogues are associated with hepatitis B surface antigen reductions, though larger trials are needed. This review proposes biomarker-guided stratification and multi-target combination strategies to improve functional cure rates in CHB.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"687-696"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Hepatitis B in the Asia-Pacific Region: Results of the 2023 Global Burden of Disease Study.","authors":"Zhengzhao Lu, Dong Xu, Wei Ji, Jingjie Zhao, Tingting Xiao, Dongxu Wang, Yuanyuan Kong, Jidong Jia, Hong You, Xinyu Zhao","doi":"10.14218/JCTH.2026.00114","DOIUrl":"10.14218/JCTH.2026.00114","url":null,"abstract":"<p><strong>Background and aims: </strong>The Asia-Pacific region accounts for a larger share of the hepatitis B burden than any other regions of the world, presenting a challenge to meeting the World Health Organization (WHO) 2030 elimination targets. In this study, we aimed to quantify the burden of chronic hepatitis B (CHB) and project its trends through 2030 using the Global Burden of Disease 2023 framework, thereby identifying gaps and priorities for the Asia-Pacific region to achieve WHO 2030 targets.</p><p><strong>Methods: </strong>Using data from the Global Burden of Disease Study 2023, we analyzed CHB prevalence, mortality, and disability-adjusted life years. We evaluated temporal trends (1990-2023) using average annual percent changes and projected the 2024-2030 burden using Bayesian age-period-cohort models.</p><p><strong>Results: </strong>In 2023, the Asia-Pacific region accounted for 63% of global CHB cases (178.0 million), 66% of deaths (259.1 thousand), and 65% of disability-adjusted life years (8.4 million). Regional prevalence and mortality rates exceeded global averages, although childhood (<5 years) prevalence was comparatively lower (590.3 vs. 1,325.3 per 100,000). East Asia bore the highest absolute burden (99.2 million cases), and South Asia had the largest pediatric caseload. Between 1990 and 2023, Western Asia showed the steepest decline in adult prevalence (-1.99%), whereas Southeast and Central Asia exhibited upward mortality trends. Projections indicate that the Asia-Pacific region is off track to meet the WHO 2030 disease elimination targets, as the prevalence rate in children under five years remains above the 0.1% target threshold and absolute mortality is projected to increase.</p><p><strong>Conclusions: </strong>The Asia-Pacific region continues to contribute the largest share of the global CHB burden and now faces persistent gaps despite progress. Although substantial progress has been made in reducing prevalence through immunization, the region is currently off track to meet the WHO 2030 targets for both incidence and mortality.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"587-600"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the 4EBP1/HSP90β/Nrf2 Axis Sensitizes β-catenin-mutant Hepatocellular Carcinoma to mTOR Inhibitors via Ferroptosis Induction.","authors":"Rong Li, Yi Zhou, Zimu Wang, Gang Liu, Deyu Fan, Lanxuan Huang, Fule Deng, Ning Wei, Runze Shang, Meng Xu","doi":"10.14218/JCTH.2026.00072","DOIUrl":"10.14218/JCTH.2026.00072","url":null,"abstract":"<p><strong>Background and aims: </strong>The aberrant activation of the mTOR pathway and its crosstalk with other signaling cascades represent key drivers of hepatocellular carcinoma (HCC) progression. mTOR-mediated ferroptosis suppression has been implicated in HCC resistance to chemotherapy. This study aimed to elucidate the mechanisms underlying mTOR inhibitor resistance and to evaluate the therapeutic potential of multidrug combinations in β-catenin-mutant HCC.</p><p><strong>Methods: </strong>MHCC97H and SNU449 cells were transfected with 4EBP1WT, 4EBP1A4, or HSP90β expression plasmids and then treated with rapamycin to assess their effects on ferroptosis and rapamycin sensitivity. The role of 4EBP1 in regulating ferroptosis was further explored by Western blotting, co-immunoprecipitation, and immunofluorescence. The inhibitory effects of mTOR inhibitors (rapamycin, MLN0128), ERK inhibitors (PD901), and their combination (MLN0128 + PD901) on tumor cells were evaluated. HCC mouse models were generated via hydrodynamic tail vein injection of c-Met/β-cateninΔN90 or c-Met/β-cateninΔN90/4EBP1A4 plasmids to evaluate the therapeutic effects of the four treatment regimens.</p><p><strong>Results: </strong>Rapamycin more potently inhibited mTOR/RPS6 than mTOR/4EBP1 and concurrently induced ferroptosis. 4EBP1A4 promoted ferroptosis and potentiated rapamycin efficacy. Mechanistically, 4EBP1A4 competitively bound HSP90β, displacing Keap1, thereby increasing Keap1-Nrf2 complex formation and promoting Nrf2 degradation. Furthermore, rapamycin, MLN0128, PD901, and their combination reduced p-4EBP1 levels, induced ferroptosis, and inhibited HCC cell proliferation, thereby suppressing tumor growth, with the combination exhibiting the strongest effect.</p><p><strong>Conclusions: </strong>4EBP1A4 enhances Nrf2 ubiquitination and degradation via the HSP90β/Keap1 axis, relieving mTOR-mediated ferroptosis suppression and synergistically improving rapamycin efficacy. Additionally, rapamycin, MLN0128, and PD901 suppress HCC progression by inducing ferroptosis, with their combination showing superior potency.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"649-664"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multi-omics and Machine Learning Framework Identifies Plasma SBDS as a Causal Biomarker and Therapeutic Target in Primary Sclerosing Cholangitis.","authors":"Pengfei Cheng, Yuanming Qiang, Yibo Sun, Binwei Duan, Yabo Ouyang, Guangming Li","doi":"10.14218/JCTH.2025.00676","DOIUrl":"10.14218/JCTH.2025.00676","url":null,"abstract":"<p><strong>Background and aims: </strong>Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease. Its molecular etiology remains poorly defined, hindering the development of mechanism-based diagnostics and therapies. Therefore, this study aimed to identify key molecular drivers and causal biomarkers of PSC by integrating transcriptomics, machine learning, and genetic causal inference.</p><p><strong>Methods: </strong>We deployed a computational framework combining transcriptomics, network biology, machine learning, and genetic causal inference. Peripheral blood transcriptomes from PSC patients and controls were analyzed to identify disease-associated modules. Candidate genes were refined via protein-protein interaction networks and a multi-algorithm machine learning screen. Causal inference was performed using two-sample Mendelian randomization, integrating plasma protein quantitative trait loci with PSC genome-wide association study summary statistics.</p><p><strong>Results: </strong>Transcriptomic analysis revealed a PSC-associated module enriched in ribosome biogenesis and protein homeostasis pathways. A machine learning-optimized nine-gene signature (including PTMA, SUMO1, Shwachman-Bodian-Diamond syndrome (SBDS), RPL7, EIF1AX, ANP32A, PCNA, FAM98A, and MPHOSPH6) achieved high diagnostic accuracy (mean AUC = 0.908) and was consistently downregulated in PSC. This signature was linked to a remodeled immune microenvironment characterized by myeloid skewing and specific transcriptional-immune covariation patterns. Mendelian randomization identified SBDS as a putatively causal protective factor, where genetically instrumented higher plasma SBDS protein levels were robustly associated with a lower PSC risk (inverse variance weighted odds ratio = 0.525, 95% CI: 0.356-0.773, <i>P</i> = 0.001). Sensitivity analyses supported the validity of the Mendelian randomization assumptions.</p><p><strong>Conclusions: </strong>Our study establishes disrupted ribosome homeostasis as a causal pathway in PSC and nominates plasma SBDS as a high-confidence diagnostic biomarker and therapeutic target. The integrative framework provides a generalizable strategy for discovering causal biomarkers in complex diseases.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 6","pages":"637-648"},"PeriodicalIF":6.0,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13384951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Simplified Prognostic Model for 90-day Transplant-free Survival in Patients with Severe Acute Liver Injury/Acute Liver Failure.","authors":"Yan Ren, Manman Xu, Wenling Wang, Ming Kong, Yu Chen","doi":"10.14218/JCTH.2026.00075","DOIUrl":"10.14218/JCTH.2026.00075","url":null,"abstract":"<p><strong>Background and aims: </strong>Early risk stratification of severe acute liver injury (SLI) that may progress to acute liver failure (ALF), is vital for timely intervention, but no universal prognostic assessment tool covers both conditions. This study aimed to develop a simplified prognostic model for early risk assessment in SLI/ALF patients.</p><p><strong>Methods: </strong>A retrospective cohort study consecutively enrolled SLI patients (including those progressing to ALF) from July 1, 2020 to May 31, 2025. Baseline clinical and laboratory data on admission were collected, with 90-day transplant-free survival as the primary outcome. Independent prognostic factors were screened via Cox regression to build a simplified scoring model, whose performance was compared with the Model for End-Stage Liver Disease (MELD), King's College Criteria (KCC), and the Acute Liver Failure Study Group Prognostic Index (ALFSG-PI).</p><p><strong>Results: </strong>Of 302 patients, 190 (62.9%) achieved 90-day transplant-free survival. Multivariate Cox regression identified international normalized ratio (hazard ratio [HR]: 1.118, 95% confidence interval [CI]: 1.050-1.191), platelet count (HR: 0.995, 95% CI: 0.993-0.998), and hepatic encephalopathy grade ≥ 2 (HR: 5.187, 95% CI: 3.403-7.907) as independent predictors, forming the HIP (derived from the above-mentioned three predictors) model. It showed good discrimination (area under the receiver operating characteristic curve [AUC]: 0.82), outperforming MELD (AUC: 0.76, <i>P</i> = 0.019) and KCC (AUC: 0.72, <i>P</i> = 0.002), and performing comparably to ALFSG-PI (AUC: 0.80, <i>P</i> = 0.429). The model also performed robustly in ALF subgroups defined by the American College of Gastroenterology and the 2024 Chinese Medical Association guidelines (AUCs: 0.80 and 0.76, respectively) and achieved an AUC of 0.85 in the validation set.</p><p><strong>Conclusions: </strong>The HIP model is a simple and effective tool for prognostic risk stratification in SLI/ALF patients, suitable for emergency and primary care to facilitate timely intervention.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 5","pages":"541-548"},"PeriodicalIF":6.0,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Dysfunction-associated Steatotic Liver Disease Diminishes the Efficacy of miR-125b-5p-engineered MSC Therapy for Hepatocellular Carcinoma via HK2 Upregulation: A Multimodal Theranostic Study.","authors":"Lishan Shen, Xiaowen Luo, Xiaorui Su, Xiang Zhou, Fengyun Zou, Shuangshuang Zhong, Yayin Deng, Boya Yin, Zhicheng Yao, Ruomi Guo","doi":"10.14218/JCTH.2025.00709","DOIUrl":"10.14218/JCTH.2025.00709","url":null,"abstract":"<p><strong>Background and aims: </strong>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for effective therapies. Although miR-125b-5p shows therapeutic potential, its efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC and the underlying mechanisms remain unclear. In this study, we aimed to develop a magnetic resonance imaging (MRI)-trackable miR-125b-5p-engineered MSC platform for HCC therapy and to determine whether MASLD attenuates its antitumor efficacy through metabolic reprogramming.</p><p><strong>Methods: </strong>Bone marrow mesenchymal stem cells (MSCs) were genetically engineered to coexpress miR-125b-5p (a therapeutic gene) and ferritin heavy chain (Fth; a MRI reporter gene), enabling sustained delivery and real-time tracking. Orthotopic HCC models with or without MASLD were established to evaluate therapeutic outcomes. In vivo MRI, histological analyses, and bioinformatics approaches were used to assess efficacy and mechanisms.</p><p><strong>Results: </strong>Transplantation of miR-125b-5p-Fth-MSCs significantly suppressed HCC growth in vivo over an extended period. However, MASLD attenuated this therapeutic effect. Mechanistically, miR-125b-5p directly targeted hexokinase 2 (HK2), inhibiting HCC proliferation and migration through suppression of the PI3K/AKT/mTOR pathway. Fatty acid-induced lipotoxicity upregulated HK2 expression and counteracted the antitumor effects of miR-125b-5p.</p><p><strong>Conclusions: </strong>Multigene-modified MSCs enable effective, MRI-monitored HCC therapy. MASLD diminishes the efficacy of miR-125b-5p through HK2 upregulation. These findings establish a multimodal theranostic framework for HCC and provide mechanistic insights into MASLD-associated therapeutic resistance.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 5","pages":"511-524"},"PeriodicalIF":6.0,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus versus Outcome-based Definitions of Acute-on-chronic Liver Failure: Implications for Risk Stratification and Case Identification.","authors":"Nipun Verma, Tingting Qi, Pratibha Garg, Arun Valsan, Gowripriya Nair, Julian Pohl, Arathi Venu, Xianbo Wang, Xin Zheng, Guohong Deng, Yan Huang, Zhongji Meng, Yanhang Gao, Zhiping Qian, Xiaobo Lu, Feng Liu, Yu Shi, Jia Shang, Yubao Zheng, Yingli He, Meiqian Hu, Changze Hong, Sina Jameie-Oskooei, Raj Mookerjee, Mohammad Mahdi Saeidinejad, Sunil Taneja, Jinjun Chen, Hai Li, Ajay Duseja, Cornelius Engelmann, Rajiv Jalan","doi":"10.14218/JCTH.2026.00267","DOIUrl":"10.14218/JCTH.2026.00267","url":null,"abstract":"<p><strong>Background and aims: </strong>Acute-on-chronic liver failure (ACLF) lacks a universally accepted definition, and recent efforts have proposed consensus organ failure criteria. In this study, we aimed to compare the clinical validity of a recently proposed consensus ACLF framework with the outcome-calibrated A-TANGO classification.</p><p><strong>Methods: </strong>We performed a multinational cohort study including 2,398 patients from the TIH cohort (India) and 2,568 from the CATCH-LIFE cohort (China) who were hospitalized with acute decompensation of cirrhosis. ACLF was defined using A-TANGO and an operationalized version of the 2025 consensus framework. Outcomes were 28- and 90-day mortality. Analyses assessed case capture, overlap, mortality risk, sensitivity, specificity, and net reclassification improvement (NRI).</p><p><strong>Results: </strong>ACLF prevalence differed substantially by definition. In TIH, A-TANGO classified 79.2% as ACLF versus 42.3% by the consensus definition; in CATCH-LIFE, the corresponding values were 31.4% versus 5.8%, respectively. Most consensus ACLF cases were captured by A-TANGO, which additionally classified 26%-37% of patients as having ACLF. These patients had substantial mortality (28-day: 18.1%-26.9%; 90-day: 33.2%-37.9%), significantly higher than those negative by both frameworks and comparable to established ACLF risk thresholds. A-TANGO showed higher sensitivity for 28-day mortality (TIH: 94.1% vs. 67.8%; CATCH-LIFE: 76.1% vs. 25.6%), whereas consensus criteria were more specific. Reclassification analyses showed improved discrimination with A-TANGO (NRI: 17.1% in TIH; 27.4% in CATCH-LIFE). Within the consensus non-ACLF group, A-TANGO further stratified patients into distinct risk groups with stepwise increase in mortality.</p><p><strong>Conclusions: </strong>In conclusion, the two frameworks identify fundamentally different populations. The consensus definition significantly reduces sensitivity and under-recognizes high-risk patients. Compared with consensus definitions, the outcome-calibrated framework better supports diagnosis, clinical decision-making, risk stratification, and trial design in ACLF.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"14 5","pages":"525-540"},"PeriodicalIF":6.0,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13247718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}