Journal of Hepatocellular Carcinoma最新文献

{"title":"Emerging Role of Sirtuins-Mediated Ferroptosis in Hepatocellular Carcinoma Progression: Mechanisms and Therapeutic Perspectives.","authors":"Jiangtao Bai, Xuefeng Bai, Jihong Yang, Guodong Yu, Yong Cui","doi":"10.2147/JHC.S595693","DOIUrl":"10.2147/JHC.S595693","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) ranks as the most common type of primary liver cancer, characterized by rapid tumor growth and therapeutic resistance. Evading cell death is a key characteristic of multiple cancers, including HCC. Many programmed cell death (PCD) processes, comprising apoptosis, autophagy, necroptosis, and ferroptosis, have been identified to affect tumor growth and recurrence of HCC. Ferroptosis is an emerging iron-dependent PCD mode characterized by lipid peroxidation and iron accumulation. It has emerged as a critical regulatory mechanism in HCC progression. Sirtuins (SIRTs), a class III histone deacetylases (HDACs) that require NAD⁺ as a cofactor, exhibit exclusive and poised functions in the pathophysiological processes of cancers by mediating ferroptosis. However, a summary of the mechanisms of SIRT-mediated ferroptosis in HCC development and associated therapeutic strategies is limited. This article provides an outline of recent developments in the role of SIRTs in HCC proliferation, metastasis, and the development of multidrug resistance. We highlight the roles and mechanisms of SIRTs in mediating ferroptosis in HCC, aiming to provide a comprehensive and novel perspective for developing diagnostic biomarkers and therapeutic strategies for HCC, thereby advancing the understanding of HCC pathogenesis and treatment.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"595693"},"PeriodicalIF":3.9,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391170","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":"Baseline Sleep Quality and Objective Response in HCC Patients Treated with TACE Combined with Lenvatinib and PD-1 Inhibitors: A Secondary Analysis of a Prospectively Registered Observational Cohort.","authors":"Pengfei Tian, He Zhao, Wei Sun, Qing Peng, Yingen Luo, Mingchen Sang, Junqing Xi, Ho-Young Song, Zhengqiang Yang","doi":"10.2147/JHC.S600627","DOIUrl":"10.2147/JHC.S600627","url":null,"abstract":"<p><strong>Background: </strong>Sleep disturbance is common in patients with cancer and may reflect host immune, inflammatory, and symptom states relevant to treatment response. In hepatocellular carcinoma (HCC), whether baseline sleep quality is associated with objective response among patients receiving transarterial chemoembolization (TACE) combined with lenvatinib and PD-1 inhibitors remains uncertain.</p><p><strong>Methods: </strong>We conducted a secondary analysis of a prospectively registered observational HCC cohort in the Chinese Clinical Trial Registry. Consecutive patients in the cohort who were treated with TACE plus lenvatinib and PD-1 inhibitors were screened; 129 patients with available baseline Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), and response data were included. Objective response rate (ORR) was assessed using modified Response Evaluation Criteria in Solid Tumors (mRECIST). Multivariable logistic regression adjusted for age, sex, ECOG performance status, ALBI grade, maximum tumor diameter, tumor number, and portal vein tumor thrombosis. Unstabilized inverse-probability complete-case weighting and multiple imputation were used as sensitivity analyses.</p><p><strong>Results: </strong>The mean age was 60.9 years, 94 patients (72.9%) were male, and 64 of 129 patients (49.6%) achieved ORR. Responders had better baseline sleep quality than non-responders (mean PSQI 4.14 vs 7.94; p<0.001). After adjustment, each 1-point increase in PSQI was associated with lower odds of ORR (OR 0.62, 95% CI 0.48-0.75; p<0.001). The association was similar after inverse-probability weighting (OR 0.63, 95% CI 0.52-0.75; p<0.001) and multiple imputation (OR 0.66, 95% CI 0.55-0.79; p<0.001). Baseline HADS-Anxiety and HADS-Depression scores were not independently associated with ORR.</p><p><strong>Conclusion: </strong>Poorer baseline sleep quality was independently associated with a lower probability of objective response in HCC patients treated with TACE plus lenvatinib and PD-1 inhibitors. PSQI may be a feasible baseline risk-stratification tool in this setting, but causal inference is limited and prospective validation is required before sleep-directed interventions can be expected to improve tumor response.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"600627"},"PeriodicalIF":3.9,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391141","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":"Machine-Learning Based Prognostic Model for Predicting Early Recurrence in HCC Patients After Hepatectomies: An Explainable AI Approach.","authors":"Heng-Yuan Hsu, Jiunn-Chang Lin, Chun-Wei Huang, Song-Fong Huang, Chun-Yi Wu, Tun-Sung Huang, Hung-Fei Lai, Ming-Chin Yu","doi":"10.2147/JHC.S618264","DOIUrl":"10.2147/JHC.S618264","url":null,"abstract":"<p><strong>Purpose: </strong>Early recurrence within 24 months post-resection remains a primary driver of poor prognosis in hepatocellular carcinoma (HCC). In the absence of standardized adjuvant guidelines, robust postoperative risk stratification is critical. We evaluated explainable machine learning (ML) architectures to optimize risk modeling using readily accessible parameters.</p><p><strong>Patients and methods: </strong>This retrospective, multicenter study analyzed 1,681 HCC patients undergoing curative-intent hepatectomy at Chang Gung institutions (2007-2020) as the training cohort. External validation was conducted using an independent cohort (n = 251) from Mackay Memorial Hospital. Four algorithms-random survival forest, Cox-nnet, LASSO, and extreme gradient boosting (XGBoost)-were trained using 5-fold cross-validation. Missing data were handled via k-nearest neighbors imputation. Discriminative capacity was assessed using the concordance index (C-index), and feature significance was decoded through SHAP values.</p><p><strong>Results: </strong>The XGBoost framework yielded optimal discrimination, achieving a high training C-index of 0.98. During independent external validation, the C-index attenuated to a robust 0.72, reflecting expected adjustments for baseline institutional heterogeneities. Multivariable Cox and SHAP analyses consistently identified five pivotal predictors: sex, preoperative treatment, tumor size, satellite lesions, and vascular invasion. The derived nomogram enabled effective patient risk-tiering (<i>p</i> < 0.0001), although absolute recurrence probabilities were systematically overestimated in the external validation cohort.</p><p><strong>Conclusion: </strong>While the XGBoost model exhibits expected calibration shifts across disparate cohorts, it provides robust, cross-center discriminative generalizability for categorical risk stratification. Rather than serving as an absolute probability estimator, this explainable model functions as a reliable clinical tool to selectively identify high-risk candidates for intensive imaging surveillance. Geographically and ethnically diverse prospective validation remains required prior to broader clinical deployment.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"618264"},"PeriodicalIF":3.9,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13314570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361248","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":"Multimodal Modeling Distinguishes Treatment Response from Overall Survival in Hepatocellular Carcinoma Receiving Combined Interventional and Targeted Immunotherapy.","authors":"Donghai Lu, Pengfei Sun, Han Li, Zeng Liang, Zhaohan Zhang, Qihang Cao, Daolin Zhang, Qiao He, Jisen Jia, Yuxuan Wang, Zhaoru Dong, Dongxu Wang, Tao Li","doi":"10.2147/JHC.S613014","DOIUrl":"10.2147/JHC.S613014","url":null,"abstract":"<p><strong>Background & aims: </strong>While combined interventional therapies and targeted immunotherapy have improved outcomes for unresectable hepatocellular carcinoma (HCC), radiographic tumor shrinkage does not guarantee prolonged survival (the \"responder paradox\"). We hypothesized that these distinct endpoints may be associated with different clinical and biological factors and require separate predictive strategies. This study aimed to develop the predictive radiomics-integrated multimodal estimation (PRIME) system to independently predict and biologically characterize treatment response versus overall survival (OS).</p><p><strong>Methods: </strong>In this multicenter study comprising 246 patients receiving combined interventional therapies and targeted immunotherapy, we integrated clinical data and dual-phase CT radiomics. We employed multimodal fusion algorithms to construct two models: PRIME-R (predicting 3-month objective response) and PRIME-S (predicting OS). Model performance was rigorously tested in an external validation cohort. Furthermore, we utilized SHapley Additive exPlanations and matched imaging-transcriptomic data to elucidate the specific clinical and molecular features associated with each outcome.</p><p><strong>Results: </strong>The PRIME models demonstrated superior accuracy compared to single-modality approaches. In external validation, PRIME-R achieved an AUC of 0.85, while PRIME-S achieved a C-index of 0.72. Significant risk stratification was confirmed (HR = 3.31, 95% CI: 2.06-5.31, P < 0.001). Crucially, feature analysis revealed a distinct divergence: PRIME-R was primarily driven by tumor morphology. In contrast, PRIME-S relied heavily on systemic inflammation and liver function reserve. Transcriptomic profiling supported this interpretation, showing that response was associated with acute immune activation, whereas survival was associated with metabolic adaptation and tissue homeostasis.</p><p><strong>Conclusion: </strong>Short-term response and long-term survival in HCC are distinct clinical endpoints associated with different biological drivers. The PRIME system effectively distinguishes these outcomes, offering insights into the responder paradox and supporting dual-endpoint risk stratification pending further prospective validation.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"613014"},"PeriodicalIF":3.9,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13294205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345327","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":"Angiogenic Prognostic Signature for Stratification in Hepatocellular Carcinoma.","authors":"Zhanwei Zhu, Cao Guo, Hong Shen, Shan Zeng, Namei Li","doi":"10.2147/JHC.S600117","DOIUrl":"10.2147/JHC.S600117","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Angiogenesis drives HCC progression, but reliable biomarkers remain limited.</p><p><strong>Methods: </strong>We analyzed angiogenesis‑related genes (ARGs) using TCGA data, constructed a prognostic signature via LASSO‑Cox regression, and validated it in ICGC and real‑world HCC cohorts. Functional experiments (in vitro and in vivo) were performed for Secretory phosphoprotein 1 (SPP1). Single‑cell RNA‑seq data mapped cellular sources of signature genes. Drug sensitivity (GDSC2) and sorafenib‑treated GEO data assessed therapy response.</p><p><strong>Results: </strong>A four-gene ARG signature (APOH, SLCO2A1, SPP1, VTN) stratified HCC patients into high- and low-risk groups with distinct survival, validated in external cohorts. The high‑risk group showed enriched immune checkpoint expression and stromal activity. Single‑cell analysis revealed SPP1 mainly from macrophages and hepatocytes; VTN, APOH, and SLCO2A1 from monocyte/macrophage subsets. SPP1 knockdown suppressed endothelial angiogenesis in vitro and in vivo. High‑risk patients exhibited reduced sorafenib sensitivity (higher IC50), and sorafenib treatment downregulated APOH, SPP1, and VTN but not SLCO2A1.</p><p><strong>Conclusion: </strong>We established a robust ARG‑based prognostic signature for HCC that improves risk stratification and highlights links between angiogenesis, immune microenvironment, and drug response.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"600117"},"PeriodicalIF":3.9,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148330462","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":"Machine Learning-Based Radiopatho-Clinical Model Integrating Ultrasound Radiomics and Kleiner Score for Prognosis Prediction in NAFLD-Related Hepatocellular Carcinoma.","authors":"Chang-Lei Li, Zhen Jia, Zhi-Yuan Yao, Xiao-Tong Cui, Ao Sun, Ao-Yun Hao, Zhong-Yi Chen, Fang Chen, Jing-Yu Cao, Zu-Sen Wang","doi":"10.2147/JHC.S611041","DOIUrl":"10.2147/JHC.S611041","url":null,"abstract":"<p><strong>Background: </strong>Nonalcoholic fatty liver disease (NAFLD) is an increasingly important etiologic factor in hepatocellular carcinoma (HCC), but the prognostic value of liver-background steatosis remains incompletely defined. We developed and internally validated an integrated machine learning model combining ultrasound radiomics, pathological steatosis grading, and clinicopathological variables for postoperative risk stratification in HCC.</p><p><strong>Methods: </strong>This retrospective study included 639 patients with HCC who underwent curative resection between 2010 and 2023. Radiomic features were extracted from preoperative ultrasound images, and a radiomics signature was generated using LASSO regression. Hepatic steatosis was graded using the Kleiner score, and clinicopathological variables were screened using the Boruta algorithm. A total of 101 machine learning models were developed and compared. Model performance was assessed using the concordance index, time-dependent area under the curve (AUC), Brier score, calibration, decision curve analysis, and SHapley Additive exPlanations.</p><p><strong>Results: </strong>The random survival forest model showed the best overall performance for predicting overall survival (OS) and recurrence-free survival (RFS). In the validation cohort, the 1-, 3-, and 5-year AUCs were 0.863, 0.794, and 0.804 for OS, and 0.828, 0.811, and 0.823 for RFS, respectively. Brier scores remained below 0.20. Compared with BCLC and CNLC staging systems, the integrated model showed improved discrimination, calibration, and net clinical benefit. SHAP analysis indicated that microvascular invasion, tumor size, AFP, INR, Kleiner score, and Radscore contributed to individualized risk prediction.</p><p><strong>Conclusion: </strong>This integrated radiopatho-clinical machine learning model showed favorable internal performance for predicting OS and RFS after curative resection. Steatosis-related features may provide complementary prognostic information, supporting individualized postoperative surveillance, although external validation is required.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"611041"},"PeriodicalIF":3.9,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317602","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":"Current Status and Emerging Trends in Global Research on Liposome Therapy for Hepatocellular Carcinoma: A Bibliometric Analysis.","authors":"Xiaotao Hong, Yibo Wu, Xiaocong Wu, Chengwei Huang, Chunsheng Li","doi":"10.2147/JHC.S608648","DOIUrl":"10.2147/JHC.S608648","url":null,"abstract":"<p><strong>Background: </strong>Liposomes are widely used as nanocarriers for targeted drug delivery in cancer therapy, including hepatocellular carcinoma (HCC). However, no comprehensive bibliometric study has systematically evaluated global research trends, major research hotspots, and clinical translation progress in liposome-based therapy for HCC.</p><p><strong>Methods: </strong>On September 29, 2025, we queried the Web of Science Core Collection for liposome and HCC publications. Using CiteSpace and VOSviewer, we analyzed trends and emerging hotspots. Additionally, we retrieved clinical trial literature on liposome therapy for HCC from the PubMed database and analyzed it to assess clinical progress in this field.</p><p><strong>Results: </strong>A total of 1116 publications related to liposome-based therapy for liver cancer were identified over the past 35 years. China ranked first in publication output, while the Chinese Academy of Sciences was the most productive institution. The International Journal of Nanomedicine published the highest number of articles, and Zhang Bo was the most prolific author. Keyword co-occurrence and citation analyses identified doxorubicin-loaded liposomes, apoptosis, pharmacokinetics, tumor microenvironment, metastasis, and glycyrrhetinic acid-mediated targeting as major research hotspots. Recent studies increasingly focused on targeted nanocarrier design, combination therapy strategies, and tumor-specific delivery systems. Clinical studies mainly investigated liposomal drugs combined with radiofrequency ablation or ultrasound hyperthermia; however, advanced clinical translation remains limited.</p><p><strong>Conclusion: </strong>This bibliometric analysis provides a comprehensive overview of global research activity in liposome-based therapy for HCC. Although substantial progress has been achieved in preclinical nanomedicine research, the limited number of clinical studies highlights a significant translational gap. Future research should prioritize improving targeting efficiency, biosafety, immune modulation, and large-scale clinical applicability of liposomal delivery systems.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"608648"},"PeriodicalIF":3.9,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317626","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":"Integrating Combination Therapy and Smart Embolic Materials to Overcome the Therapeutic Ceiling of Transarterial Chemoembolization in Hepatocellular Carcinoma.","authors":"Yantao Fu, Chenglin Bai, Yunzhi Ling, Yijun Liu, Weijun Li, Guoming Li","doi":"10.2147/JHC.S620956","DOIUrl":"10.2147/JHC.S620956","url":null,"abstract":"<p><p>Transarterial chemoembolization (TACE) remains standard for intermediate-stage hepatocellular carcinoma (HCC), but its long-term efficacy is limited by post-embolic hypoxia-driven angiogenesis and high recurrence rates. Combining TACE with targeted therapy, immunotherapy, or ablation improves outcomes. Concurrently, smart embolic agents are transforming TACE from passive embolization into active modulation of the tumor microenvironment. This review systematically evaluates clinical evidence for TACE-based combinations and principles guiding individualized selection. We delineate synergistic mechanisms of TACE with systemic and locoregional therapies, and highlight functional design of novel embolic materials. Although some triplet regimens have shown progression-free survival benefits, overall survival superiority remains unproven, as exemplified by the negative OS outcome in the LEAP-012 trial. However, the available network meta-analyses are constrained by substantial heterogeneity in study design, TACE protocols, and outcome definitions, warranting cautious interpretation. Finally, we propose a multidisciplinary paradigm integrating interventional radiology, diagnostic imaging, and biomaterials science. The convergence of material innovation and combination optimization holds promise for overcoming TACE's therapeutic ceiling.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"620956"},"PeriodicalIF":3.9,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13289639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317651","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":"Putative Imprinting Control Regions with Aberrant Blood-Based DNA Methylation are Associated with Hepatocellular Carcinoma Risk.","authors":"Annie J DiFrank, Bruce A Corliss, James J H Park, Molly Rogers, David A Skaar, Dereje D Jima, Michael Cowley, Susan K Murphy, Andrew Liu, Cynthia A Moylan, Cathrine Hoyo","doi":"10.2147/JHC.S605131","DOIUrl":"10.2147/JHC.S605131","url":null,"abstract":"<p><strong>Introduction: </strong>Site-specific 5-methylcytosine levels measured in blood can be suitable surrogate markers for epigenetic alterations in inaccessible tissues and are associated with hepatocellular carcinoma (HCC) risk. However, replication has been limited due to prior low genomic coverage and the tissue-specific nature of methylation at many CpG sites. One exception is imprinting control regions (ICRs), which use stable, early-onset methylation to regulate monoallelic expression across somatic tissues, implying aberrant methylation at ICRs detected in blood may be relevant to liver disease.</p><p><strong>Purpose: </strong>Leveraging primary HCC samples, we aimed to identify putative ICRs with aberrant DNA methylation associated with HCC to inform development of a blood-based risk stratification panel for earlier detection and clinical triage.</p><p><strong>Participants and methods: </strong>Whole genome bisulfite sequencing (WGBS) was performed on leukocyte-derived DNA of 10 primary HCC cases and 51 controls to identify differential methylation. An independent comparison of 29 primary HCC cases and 36 controls was used to validate differential methylation measured in leukocytes using the novel Human Imprintome Methylation Array.</p><p><strong>Results: </strong>We identified 1,519 differentially methylated regions associated with HCC by WGBS (FDR p < 0.05), which mapped to 81 putative ICRs, the majority of which had not previously been linked to HCC. Comparison with published studies further established 16 putative ICRs that have previously been associated with HCC or precancerous chronic liver disease states for a total of 97 loci. Validation using the Human Imprintome Methylation Array replicated 46 (57%) of these regions (FDR p < 0.05). Nearest genes were enriched for pathways related to liver disease including liver hyperplasia, hepatitis, steatosis, and HCC.</p><p><strong>Conclusion: </strong>Our comprehensive genome profiling identified aberrant methylation at putative ICRs in blood that were associated with HCC. These findings support the hypothesis that ICRs, which exhibit relatively stable methylation across tissues, warrant further investigation as early blood-based HCC biomarkers.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"605131"},"PeriodicalIF":3.9,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13286735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148317573","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":"Hepatocellular Carcinoma Precursor Lesions: From Pathological Basis to Risk Stratification and Precision Intervention.","authors":"Ruijuan Yan, Haibo Zhang, Junzhe Jiao, Qian Huang, Ning Wang, Jianfeng Bao, Xiaojiaoyang Li, Shuguang Yan, Jingtao Li","doi":"10.2147/JHC.S613101","DOIUrl":"10.2147/JHC.S613101","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) predominantly arises against a background of chronic liver disease and cirrhosis, with its development typically following the three-step pattern of \"hepatitis-cirrhosis-liver cancer.\" Hepatocellular carcinoma precursor lesions represent a critical stage in this process and constitute a vital window for early diagnosis and targeted intervention. This review aims to systematically summarize the pathological basis, malignant potential, diagnostic approaches, risk stratification strategies, and precision intervention perspectives of HCC precursor lesions. Specifically, we review the pathological characteristics and malignant potential of HCC precursor lesions such as hepatocellular large/small cell transformation, dysplastic foci (DF), low/high-grade dysplastic nodules (LGDN/HGDN), and β-catenin-activated hepatocellular adenoma. We further summarize the application value and limitations of ultrasound/contrast-enhanced ultrasound (US), computed tomography (CT), and Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in screening and differential diagnosis. In addition, we discuss the progress in serum markers such as AFP, AFP-L3, DCP, and GP73, as well as liquid biopsy markers including CTC, ctDNA methylation, cfRNA, and tumor metabolites. We also outline the application of multivariable risk models like age-Male-ALBI-Platelet (aMAP), Gender-Age-AFP-L3-AFP-DCP (GALAD), and THRI in risk stratification and dynamic monitoring of high-risk populations. Finally, we review current treatment and follow-up strategies for HCC precursor lesions and explore the potential of radiomics, artificial intelligence, and multi-omics integration to improve risk assessment and diagnostic support, while also discussing their current limitations and the gap between research findings and routine clinical implementation. Overall, HCC precursor lesions represent an important target for early surveillance and precise intervention, and the integrated application of pathology, imaging, biomarkers, risk models, and emerging technologies may improve early identification, individualized management, and future translational research in HCC.</p>","PeriodicalId":15906,"journal":{"name":"Journal of Hepatocellular Carcinoma","volume":"13 ","pages":"613101"},"PeriodicalIF":3.9,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308492","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}