Hepatology International最新文献

{"title":"The benefit of conversion therapy for patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab using newly established oncological resectability criteria in Japan.","authors":"Shigeo Shimose, Issei Saeki, Takanori Ito, Yasuto Takeuchi, Joji Tani, Tetsu Tomonari, Ryu Sasaki, Kyo Sasaki, Satoru Kakizaki, Takeshi Hatanaka, Hideki Iwamoto, Norikazu Tanabe, Takafumi Yamamoto, Atsushi Naganuma, Tomotake Shirono, Yuki Kanayama, Sohji Nishina, Tetsuji Takayama, Hideki Kobara, Motoyuki Otsuka, Hiroki Kawashima, Taro Takami, Takumi Kawaguchi","doi":"10.1007/s12072-025-10781-y","DOIUrl":"10.1007/s12072-025-10781-y","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to investigate the changes in oncological resection status in patients with unresectable hepatocellular carcinoma (u-HCC) receiving atezolizumab plus bevacizumab (Atez/Bev) and the impact of conversion therapy following Atez/Bev treatment.</p><p><strong>Methods: </strong>This cohort included 631 patients with u-HCC treated with Atez/Bev. Tumors were assessed using oncological resectability criteria and categorized as borderline resectable 1 (BR1, n=166) or borderline resectable 2 (BR2, n=465).</p><p><strong>Results: </strong>Overall, 129 (20.4%) patients were downstaged based on oncological resectability criteria. Among them, 28 (16.8%) patients were downstaged from BR1 to resectable (R), and 49 (10.5%) and 52 (11.1%) patients were downstaged from BR2 to R and from BR2 to BR1, respectively. The percentage of patients who underwent conversion therapy was 5.4%. For patients categorized as BR1 and BR2 before Atez/Bev treatment, the rates of conversion therapy were 8.4% (14/166) and 4.3% (20/465), respectively. Overall survival (OS) was significantly higher in the conversion therapy group than in the partial response group (not reached vs. 36.4 months, p=0.001), with no significant differences compared to the complete response group. The median recurrence-free survival was 15.7 months after conversion therapy. Although there were differences in patient background data at the time of conversion therapy, surgery had a significantly higher RFS than radiofrequency ablation (not reached vs. 10.0 months, p=0.008).</p><p><strong>Conclusions: </strong>When feasible, conversion therapy should be considered to improve the prognosis of u-HCC patients treated with Atez/Bev. Moreover, oncological resectability criteria may provide a useful tool for investigators regarding conversion therapy.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"846-855"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive value of neutrophil-to-lymphocyte ratio in recurrent HCC after repeat hepatectomy or salvage liver transplantation.","authors":"Jiafeng Chen, Yuan Fang, Zheng Tang, Enfu Dong, Jun Gao, Guiqi Zhu, Pascal Kwangwari, Shanru Feng, Weifeng Qu, Xiaoling Wu, Shengwei Mao, Qianfu Zhao, Yi Wang, Rui Yang, Zhiqi Guan, Tianhao Chu, Yichao Bu, Jian Zhou, Jia Fan, Xiutao Fu, Weiren Liu, Zhenbin Ding, Yinghong Shi","doi":"10.1007/s12072-025-10786-7","DOIUrl":"10.1007/s12072-025-10786-7","url":null,"abstract":"<p><strong>Backgrounds and aims: </strong>Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, characterized by a high rate of recurrence. This study aims to compare the efficacy and safety of repeat hepatectomy (RH) and salvage liver transplantation (sLT) for recurrent hepatocellular carcinoma (rHCC) and explores the predictive value of neutrophil-to-lymphocyte ratio (NLR) and neutrophil extracellular traps (NETs).</p><p><strong>Methods: </strong>In this study, consecutive patients receiving RH (n = 637) or sLT (n = 53) for rHCC within the University of California San Francisco (UCSF) Criteria were recruited. After propensity score matching (PSM), disease-free survival (DFS) and overall survival (OS) were compared utilizing the Kaplan-Meier method. Additionally, the level of neutrophil infiltration and NETs were analyzed by multiplex immunofluorescence.</p><p><strong>Results: </strong>After PSM, the sLT group demonstrated superior 5-year DFS and OS compared to the RH group (p < 0.001 and p = 0.014). Subgroup analysis demonstrated that NLR > 2.3 was associated with poorer OS (p < 0.001 in the RH group and p = 0.024 in the sLT group) and DFS (p = 0.002 in both groups). Furthermore, we identified that patients in the sLT group are more susceptible to extrahepatic metastasis. In addition, our results revealed that higher infiltration of intratumoral neutrophils was negatively correlated with OS and DFS (p = 0.002 and p = 0.001, respectively), especially in cases with higher NETs level.</p><p><strong>Conclusions: </strong>This study indicates that sLT achieves better long-term outcomes than RH for rHCC. NLR and NETs formation are promising prognostic factors for HCC.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"856-865"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tenofovir alafenamide-related hyperlipidemia and cardiovascular risk.","authors":"Ankur Jindal, Manoj Kumar","doi":"10.1007/s12072-025-10874-8","DOIUrl":"10.1007/s12072-025-10874-8","url":null,"abstract":"","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"701-703"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging therapies for HBsAg seroclearance: spotlight on novel combination strategies.","authors":"Rex Wan-Hin Hui, James Fung, Wai-Kay Seto, Man-Fung Yuen, Lung-Yi Mak","doi":"10.1007/s12072-025-10828-0","DOIUrl":"10.1007/s12072-025-10828-0","url":null,"abstract":"<p><strong>Introduction: </strong>Functional cure is a favorable endpoint in chronic hepatitis B (CHB), yet it is rarely achieved with currently approved drugs (nucleos[t]ide analogues and pegylated interferon alpha). A range of novel agents, broadly classified into virus-targeting agents and immunomodulators, are hence developed with functional cure as the treatment target. As the data on individual novel agents are maturing, the field has gradually shifted to novel combination strategies.</p><p><strong>Methods: </strong>This article comprehensively reviewed the data on novel combination strategies against CHB. Potential mechanisms and future developmental directions are also discussed RESULTS: RNA silencers (including antisense oligonucleotides and small-interfering RNAs) form the backbone of most combination strategies. Synergistic effects are observable with the combination of RNA silencers + single or dual immunomodulators, primarily through enhancing the magnitude and rate of hepatitis B surface antigen (HBsAg) decline, prolonging RNA silencer effects, and reducing HBsAg rebound after end-of-treatment. Accumulating data also demonstrate immune dysfunction recovery among patients with significant HBsAg reduction on RNA silencer-based or immune checkpoint inhibitor-based combination therapies.</p><p><strong>Conclusion: </strong>Functional cure is now an attainable endpoint with novel combination treatment. Research is warranted to optimize combination regimens, and personalization of treatment strategies will be necessary. With further development, novel combination strategies have the potential to transform future CHB management.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"704-719"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of radiotherapy versus transarterial chemoembolization in combination with lenvatinib and camrelizumab for hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: a multicenter study.","authors":"Qizhen Huang, Xiaohong Zhong, Shaoxing Chen, Wenhui Liu, Jing Yang, Qingjing Chen, Tingting Yang, Fuqun Wei, Juhui Chen, Yufei Zhou, Lijuan Zhan, Xiuhui Liang, Jianji Pan, Kongying Lin, Jinsheng Hong, Yongyi Zeng","doi":"10.1007/s12072-025-10794-7","DOIUrl":"10.1007/s12072-025-10794-7","url":null,"abstract":"<p><strong>Background and purpose: </strong>This study aims to compare the efficacy and safety of radiotherapy (RT) and transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) with inferior vena cava/right atrium tumor thrombus (IVC/RATT) treated with lenvatinib and camrelizumab.</p><p><strong>Materials and methods: </strong>HCC with IVC/RATT from four hospitals were enrolled in this retrospective study. The patients were divided into RT group and TACE group. Stabilized inverse probability of treatment weighting (sIPTW) was used to minimize bias. The primary endpoints were overall survival (OS) and progression free survival (PFS). The second endpoints were objective response rate (ORR) and disease control rate (DCR). In addition, safety was assessed by treatment-related adverse events (TRAEs) between the two groups.</p><p><strong>Results: </strong>Among 108 patients included in this study, 48 patients in TACE group and 60 patients in RT group. The median follow-up time was 24.8 months. After the application of sIPTW, baseline characteristics were well-balanced between the two groups. Before and after sITPW, the median OS and median PFS in the RT group were significantly longer than in the TACE group. Multivariate Cox analysis showed that RT was an independent prognosis factor of both OS and PFS. There was no significant difference between two groups in overall response, while IVC/RATT response rate of RT group was significantly higher than TACE group. Incidence rate of TRAEs in two groups were similar.</p><p><strong>Conclusions: </strong>In combination with lenvatinib and camrelizumab, RT significantly improves the prognosis of HCC with IVC/RATT compared to TACE, with a comparable safety profile.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"877-887"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of tenofovir alafenamide in the context of hyperlipidemia and cardiovascular diseases: a nationwide analysis.","authors":"Jae-Young Kim, Hyuk Kim, Jeong-Ju Yoo, Sang Gyune Kim, Young-Seok Kim","doi":"10.1007/s12072-025-10809-3","DOIUrl":"10.1007/s12072-025-10809-3","url":null,"abstract":"<p><strong>Background: </strong>Despite numerous small-scale studies, the correlation between tenofovir alafenamide fumarate (TAF) and hyperlipidemia remains still limited. This study aims to evaluate the safety of TAF regarding hyperlipidemia and cardiovascular diseases using a nationwide cohort.</p><p><strong>Methods: </strong>We conducted a retrospective analysis of claims data from the Health Insurance Review and Assessment Service, comparing incidence rates of hyperlipidemia and major adverse cardiovascular events (MACE) using 1:1 propensity score matching between TAF and tenofovir disoproxil fumarate (TDF) users.</p><p><strong>Results: </strong>The incidence of hyperlipidemia among TAF users was 21.38 per 1000 person-years, compared to 10.04 among TDF users. The incidence rate ratio (IRR) was 2.13 (95% confidence interval [CI] 1.92-2.36), indicating a significantly higher incidence in TAF users compared to TDF users (p < 0.001). After adjusting for other factors, Cox regression analysis showed that TAF was significantly associated with hyperlipidemia compared to TDF (hazard ratio [HR] 1.99, 95% CI 1.79-2.20, p < 0.001). There was no significant difference in the incidence of MACE between TDF and TAF users (2.19 per 1,000 person-years for TDF and 2.25 per 1,000 person-years for TAF, IRR 1.02, 95% CI 0.79-1.33, p = 0.853), with Cox regression analysis showing no disparity between the groups (HR 1.03, 95% CI 0.78-1.36, p = 0.829).</p><p><strong>Conclusions: </strong>TAF is associated with a higher incidence of hyperlipidemia than TDF. While the incidence of MACE in the TAF group has not shown a significant increase compared to the TDF group, further investigation into long-term outcomes is warranted. Lipid monitoring in TAF and TDF patients is essential for managing risks and reducing cardiovascular complications.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"959-967"},"PeriodicalIF":6.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the hepatic fibrosis-hepatocellular carcinoma axis: from mechanisms to therapeutic opportunities.","authors":"Anqi Lin, Minying Xiong, Bufu Tang, Aimin Jiang, Junyi Shen, Zaoqu Liu, Quan Cheng, Jian Zhang, Peng Luo","doi":"10.1007/s12072-025-10838-y","DOIUrl":"10.1007/s12072-025-10838-y","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent malignant neoplasm globally and represents the third-leading cause of cancer-associated mortality worldwide. Epidemiological data indicate that 80-90% of HCC cases demonstrate documented progression from hepatic fibrosis or cirrhosis. This fibrotic-carcinogenic continuum represents a complex multistep pathological cascade, with mechanistic insights being progressively revealed through contemporary investigations.</p><p><strong>Objective: </strong>This review systematically elucidates the mechanistic contributions of dysregulated signaling pathways and immune microenvironmental remodeling during hepatic fibrocarcinogenesis.</p><p><strong>Methods: </strong>A systematic online screening protocol was implemented across multiple biomedical databases to curate relevant studies elucidating mechanisms underlying fibrosis-driven hepatocarcinogenesis.</p><p><strong>Results: </strong>This work conducts a comprehensive pathophysiological analysis of hepatic fibrosis-HCC transition, including dysregulated cytokine networks, dynamic extracellular matrix (ECM) remodeling, epigenetic dysregulation, immune landscape reprogramming, persistent oxidative stress, and acquired mitochondrial dysfunction. The analysis comprehensively evaluates widely utilized experimental models in fibrotic liver carcinogenesis research, while critically assessing emerging biomarkers and mechanism-based therapeutic targets.</p><p><strong>Conclusion: </strong>This synthesis lays conceptual foundations for advancing translational research on biomarker discovery and precision therapeutics, while offering substantive guidance for developing mechanistically informed strategies to optimize clinical outcomes in hepatic fibrosis and HCC management.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"732-759"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Explainable attention-enhanced heuristic paradigm for multi-view prognostic risk score development in hepatocellular carcinoma.","authors":"Anran Liu, Jiang Zhang, Tong Li, Danyang Zheng, Yihong Ling, Lianghe Lu, Yuanpeng Zhang, Jing Cai","doi":"10.1007/s12072-025-10793-8","DOIUrl":"10.1007/s12072-025-10793-8","url":null,"abstract":"<p><strong>Purpose: </strong>Existing prognostic staging systems depend on expensive manual extraction by pathologists, potentially overlooking latent patterns critical for prognosis, or use black-box deep learning models, limiting clinical acceptance. This study introduces a novel deep learning-assisted paradigm that complements existing approaches by generating interpretable, multi-view risk scores to stratify prognostic risk in hepatocellular carcinoma (HCC) patients.</p><p><strong>Methods: </strong>510 HCC patients were enrolled in an internal dataset (SYSUCC) as training and validation cohorts to develop the Hybrid Deep Score (HDS). The Attention Activator (ATAT) was designed to heuristically identify tissues with high prognostic risk, and a multi-view risk-scoring system based on ATAT established HDS from microscopic to macroscopic levels. HDS was also validated on an external testing cohort (TCGA-LIHC) with 341 HCC patients. We assessed prognostic significance using Cox regression and the concordance index (c-index).</p><p><strong>Results: </strong>The ATAT first heuristically identified regions where necrosis, lymphocytes, and tumor tissues converge, particularly focusing on their junctions in high-risk patients. From this, this study developed three independent risk factors: microscopic morphological, co-localization, and deep global indicators, which were concatenated and then input into a neural network to generate the final HDS for each patient. The HDS demonstrated competitive results with hazard ratios (HR) (HR 3.24, 95% confidence interval (CI) 1.91-5.43 in SYSUCC; HR 2.34, 95% CI 1.58-3.47 in TCGA-LIHC) and c-index values (0.751 in SYSUCC; 0.729 in TCGA-LIHC) for Disease-Free Survival (DFS). Furthermore, integrating HDS into existing clinical staging systems allows for more refined stratification, which enables the identification of potential high-risk patients within low-risk groups.</p><p><strong>Conclusion: </strong>This novel paradigm, from identifying high-risk tissues to constructing prognostic risk scores, offers fresh insights into HCC research. Additionally, the integration of HDS complements the existing clinical staging system by facilitating more detailed stratification in DFS and Overall Survival (OS).</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"866-876"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted APT8(16-34) obtained by cell-SELEX and its internalization with miR-23-5p into activated hepatic stellate cells.","authors":"Xue Yang, Lu Huang, Li-Qing Yang, Si-Yuan Wu, Ling Huang, Jiao-Jiao Wang, Bo-Tao Li, Ying Wang, Xiao-Lian Wang, Yi-Ran Ni, Rui-Tao Zhang, Yan-Qiong Zhang, Hong-Bing Zhang, Bo-Qing Zhang, Lan Ma, Jiang-Feng Wu, Chuan-Lin Jiang","doi":"10.1007/s12072-024-10760-9","DOIUrl":"10.1007/s12072-024-10760-9","url":null,"abstract":"<p><strong>Background: </strong>The activation of hepatic stellate cells play a pivotal role in the pathogenesis of hepatic fibrosis. However, the current lack of specifically identified targets on these cells poses a significant challenge in developing targeted delivery tools for effective anti-hepatic fibrosis therapeutics in clinical practice.</p><p><strong>Methods: </strong>Cell-systematic evolution of ligands by exponential enrichment method was conducted on HSC-T6 cell line to screen out activated hepatic stellate cell-specific aptamers. The specificity of the selected aptamers in targeting hepatic stellate cells was confirmed after truncation optimization. Furthermore, the optimal aptamer was conjugated with miR-23b-5p via C6 linkage to evaluate the targeting specificity of this complex and assess its potential in downregulating liver fibrosis-related proteins and slowing down the progression of liver fibrosis.</p><p><strong>Results: </strong>The present study successful identified 11 highly enriched single-stranded DNA sequences (APT1-11) that specifically target activated hepatic stellate cells. Subsequent affinity detection and optimization truncation led to the selection of APT8(16-34), which effectively targeted activated hepatic stellate cells both in vivo and in vitro. Moreover, when conjugated with miR-23b-5p, APT8(16-34) also exhibited internalization ability into activated hepatic stellate cells. The delivered cargo miR-23b-5p by APT8 (16-34) effectively targeted to mRNA, leading to translational inhibition and subsequent downregulation of related proteins.</p><p><strong>Conclusions: </strong>We have identified APT8 (16- 34), which exhibits specific targeting and internalization capabilities into activated hepatic stellate cells. Moreover, when conjugated with miR-23b-5p, APT8 (16-34) also internalizes into activated hepatic stellate cells, enabling miR-23b-5p exert their respective functions.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"944-958"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A robust diagnostic model for high-risk MASH: integrating clinical parameters and circulating biomarkers through a multi-omics approach.","authors":"Jie Zhang, Wei Wang, Xiao-Qing Wang, Hai-Rong Hao, Wen Hu, Zong-Li Ding, Li Dong, Hui Liang, Yi-Yuan Zhang, Lian-Hua Kong, Ying Xie","doi":"10.1007/s12072-025-10792-9","DOIUrl":"10.1007/s12072-025-10792-9","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a critical health concern, with metabolic dysfunction-associated steatohepatitis (MASH) representing a severe subtype that poses significant risks. This study aims to develop a robust diagnostic model for high-risk MASH utilizing a multi-omics approach.</p><p><strong>Methods: </strong>We initiated proteomic analysis to select differential proteins, followed by liver transcriptional profiling to localize these proteins. An intersection of differential proteins and liver-expressed genes facilitated the identification of candidate biomarkers. Subsequently, scRNA-seq data helped ascertain the subcellular localization of these biomarkers in kupffer cells. We then established two MASLD models to investigate the co-localization of F4/80 and the target proteins in Kupffer cells using immunofluorescence dual-labeling. Correlation analyses were performed using blood samples from a discovery cohort of 144 individuals with liver pathology to validate the relationships between candidate biomarkers and MASLD phenotypes. Using LASSO regression, we established the ABD-LTyG predictive model for high-risk MASH (NAS ≥ 4 + F ≥ 2) and validated its efficacy in an independent cohort of 171 individuals. Finally, we compared this model against three classic non-invasive liver fibrosis diagnostic methods.</p><p><strong>Results: </strong>A proteo-transcriptomic comparison identified 58 consistent biomarkers in plasma and liver, with 25 closely associated with MASLD phenotype. Utilizing single-cell data and the HPA database, we delineated the localization of these biomarkers in liver cells, identifying TREM2, IL18BP, and LGALS3BP predominantly in the Kupffer cell subpopulation. Validation in animal models confirmed elevated expression and cellular localization of TREM2, IL18BP, and LGALS3BP in MASLD. To enhance diagnostic capability, we integrated clinical characteristics using LASSO regression to develop the ABD-LTyG model, comprising AST, BMI, total bilirubin (TB), vitamin D, TyG, and the biomarkers LGALS3BP and TREM2. This model demonstrated an AUC of 0.832 (95% CI 0.753-0.911) in the discovery cohort and 0.807 (95% CI 0.742-0.872) in the validation cohort for diagnosing high-risk MASH, outperforming traditional assessments such as FIB-4, NFS, and APRI.</p><p><strong>Conclusion: </strong>The integration of circulating biomarkers and clinical parameters into the ABD-LTyG model offers a promising approach for diagnosing high-risk MASH. This study underscores the importance of multi-omics strategies in enhancing diagnostic accuracy and guiding clinical decision-making.</p>","PeriodicalId":12901,"journal":{"name":"Hepatology International","volume":" ","pages":"820-835"},"PeriodicalIF":5.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}