Hepatocellular carcinoma (HCC) exhibits substantial molecular and morphological heterogeneity. The recently updated 6th edition of the World Health Organization Classification of Digestive Tumours recognizes nine specific HCC subtypes, each characterized by distinct morphomolecular and clinical profiles. Although these subtypes account for approximately 35% of all HCC cases, the remaining 65% are classified as conventional HCCs.
These subtypes are categorized based on their prognostic implications: the unfavorable prognosis group comprises macrotrabecular-massive, sarcomatoid, and neutrophil-rich HCCs; the comparable prognosis group includes steatohepatitic, fibrolamellar, and chromophobe HCCs; and the favorable prognosis group consists of lymphocyte-rich and clear cell HCCs. By contrast, scirrhous HCC is associated with various clinical outcomes. Furthermore, this classification includes two newly recognized patterns: vessels encapsulating tumor clusters and CTNNB1-mutated HCC.
The imaging features of HCC are significantly correlated with its molecular-pathological characteristics. In particular, aggressive subtypes frequently present with specific imaging hallmarks such as rim arterial phase hyperenhancement, diffuse arterial phase hypo-enhancement, and intratumoral necrosis on T2-weighted imaging, which serve as critical noninvasive predictors of clinical outcomes. However, a definitive diagnosis of specific subtypes based solely on imaging remains challenging. This review provides a comprehensive overview of the molecular, pathological, and radiological characteristics of HCC subtypes and patterns, emphasizing that a detailed understanding of these features is essential for informed therapeutic decision-making and accurate prognostic assessment.
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Integration of histopathology and molecular features for the classification of benign and malignant hepatocellular neoplasms Christine Sempoux, Young Nyun Park Virchows Archiv.2026;[Epub] CrossRef
Background/Aims Wilson’s disease (WD) is an inherited and treatable disorder of copper metabolism with hepatic or neurological manifestations. It continues to pose challenges in clinical management, and long-term outcome data remain limited. This study investigated hepatic involvement and clinical outcomes in cohorts from Taiwan.
Methods Longitudinal data from 146 patients with WD, retrieved from the medical database of a tertiary referral center, were analyzed (mean age at diagnosis 20.7 ± 12.4 years; mean follow-up 16.8 ± 10.8 years; maximum 51.8 years). All patients received standard treatment and care.
Results Nine patients (6.2%) underwent liver transplantation, 6 patients (4.1%) died, and 3 patients (2.1%) developed hepatocellular carcinoma (HCC). Thrombocytopenia <100 K/μL at diagnosis was associated with reduced survival (P=0.0001). Univariate Cox regression identified thrombocytopenia at diagnosis as a strong predictor of liver transplantation or death (P = 0.0001; hazard ratio (HR): 8.41; 95% CI: 2.97–23.78). Consistently, thrombocytopenia <100 K/μL was associated with reduced survival (P < 0.0001) in an external cohort of 155 patients. In the original cohort, the estimated annual HCC risk was 0.12% (95% CI: 0.03−0.36), increasing to 0.86% (95% CI: 0.18−2.5) in those with thrombocytopenia at diagnosis (P=0.029). An exploratory Firth penalized logistic regression showed that older age at diagnosis was associated with higher odds of developing HCC (odds ratio: 1.096; 95% CI: 1.009–1.191; P = 0.031).
Conclusion WD patients have a high rate of liver fibrosis, regardless of whether they present with neurological and hepatic symptoms, and are at risk of developing HCC, warranting lifelong hepatic surveillance.
Background/Aims Local ablation therapies (LATs), including radiofrequency (RFA) and microwave ablation (MWA), are established for small hepatocellular carcinoma (HCC) as standard treatment. External beam radiotherapy (EBRT), including stereotactic body radiotherapy (SBRT) and proton beam therapy (PBT), has emerged as a non-invasive alternative; however, direct comparative evidence remains limited. We conducted a systematic review and meta-analysis comparing the efficacy and safety of EBRT versus LAT in patients with HCC.
Methods PubMed/MEDLINE, Embase, Cochrane Library, and KoreaMed were searched through June 2025 per PRISMA guidelines. Eligible studies included retrospective or prospective comparisons of EBRT (SBRT/PBT) with LAT (RFA/MWA) reporting recurrence or survival. Hazard ratios (HRs) and odds ratios (ORs) were pooled using random-effects models.
Results Twelve studies (2,768) patients were included. Compared with LAT, EBRT was associated with significantly lower local recurrence (OR 0.36, 95% confidence interval [CI] 0.25–0.50; P<0.001; I² = 0%) and improved local progression-free survival (HR 0.41, 95% CI 0.34–0.50; P <0.001), regardless of tumor size. Progression-free survival favored EBRT (HR 0.80, 95% CI 0.64–1.00; P = 0.049), whereas overall survival did not differ significantly between modalities (HR 1.24, 95% CI 0.83–1.84; P = 0.291). Severe toxicities (grade ≥3) were comparable between groups for acute (OR 0.78, 95% CI 0.27–2.24) and late events (OR 1.29, 95% CI 0.85–1.95).
Conclusions EBRT was associated with better local control without significant differences in survival or toxicity compared with LAT. These findings support the safety and efficacy of EBRT for local treatment of patients with liver-confined HCC.
Background/Aims In adults with steatotic liver disease (SLD), the hepatic impact of transitioning between combustible cigarettes (CCs) and noncombustible nicotine or tobacco products (NNTPs) remains unclear. We examined CC-NNTP transitions and liver-related events (LREs).
Methods From the Korean National Health Insurance Service, 502,198 adults with SLD and at least one cardiometabolic risk factor completing health screenings during both 2012-2013 and 2019-2020 were followed through December 2023. Seven mutually exclusive groups were defined by CC status and NNTP use; the primary outcome was LRE, including hepatocellular carcinoma and liver cirrhosis. Cox proportional hazards regression, propensity-score matching (PSM), and counterfactual mediation analysis were performed.
Results Among 502,198 participants (mean age 57.9 years; 65.6% male), 2,549 LREs occurred over a median 3.0-year follow-up. Compared with never-smokers, continuous CC smokers without NNTP use had the highest LRE risk (aHR, 1.51; 95% confidence interval (CI), 1.34-1.70), followed by CC initiators (1.45; 1.17-1.79) and CC quitters (1.28; 1.12-1.46) without NNTPs. CC quitters with NNTP use showed a lower LRE risk than continuous CC smokers without NNTP use in the full cohort (aHR, 0.65; 95% CI, 0.43-0.99), but this association was not statistically significant under PSM (aHR, 0.65; 95% CI, 0.39-1.09). Within-group PSM of NNTP versus nonuse was nonsignificant across all CC categories.
Conclusions CC cessation was associated with lower LRE risk than continued CC smoking, even among those who transitioned to NNTPs. However, NNTP use showed no independent protective association, supporting complete tobacco/nicotine abstinence as the preferred goal.
Background/Aims Recurrence is a major factor limiting the long-term survival of patients with intrahepatic cholangiocarcinoma (ICC). The molecular characteristics and potential therapeutic targets in ICC remain largely undefined.
Methods Following our previous whole-exome sequencing study, we performed targeted sequencing, Sanger sequencing, and quantitative PCR to assess all coding exons and copy number variations of LATS2 in 400 primary ICC samples. Kaplan–Meier survival curves were used to assess the impact of LATS2 mutation, copy number loss, and low expression levels on recurrence-free survival and overall survival in ICC patients. In addition, we investigated the functional role and underlying mechanisms of LATS2 variation in ICC tumor progression and resistance to anti-PD-1 therapy.
Results Among a total of 400 ICC cases, the overall frequencies of LATS2 somatic mutation and copy number loss were 3% (12/400) and 34% (136/400), respectively. Both types of variation were correlated with decreased LATS2 protein expression, increased tumor recurrence, and poor overall survival. Biofunctional investigations revealed a tumor-suppressor role of LATS2. Inactivation of LATS2 suppressed the Hippo signaling pathway, leading to aberrant activation of YAP, which upregulated PD-L1 expression and CCL2 secretion, suppressed CD8+ T cell infiltration, and enhanced recruitment of M2-like macrophages, thereby promoting immune evasion, tumor progression, and resistance to anti-PD-1 therapy.
Conclusions Our study reveals a pivotal clinical association and mechanistic role of LATS2-inactivating variation in ICC, which may serve as a useful biomarker for precision therapy.
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Multi-omics analysis identifies GINS1 as a prognostic biomarker in lung adenocarcinoma, linked to macrophage polarization and tumor cell survival Qi Xu, Yantao Jiang, Qingwu Du, Jingya Wang, Cong Wang, Tingting Qin Discover Oncology.2026;[Epub] CrossRef
Background/Aims Lenvatinib resistance and immune exclusion limit outcomes in hepatocellular carcinoma (HCC). We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and programmed cell death protein 1 (PD-1) blockade.
Methods We established lenvatinib-sensitive/lenvatinib-resistant (LS/LR) HCC models and employed multi-omics (proteomics/RNA-seq), chromatin immunoprecipitation, luciferase, and RNA immunoprecipitation assays to map hexokinase domain containing protein 1 (HKDC1) regulation. Tumor immunity was profiled by scRNA-seq, multiplex fluorescent immunohistochemistry, and flow cytometry. Spermidine (SPD)+lenvatinib efficacy was tested in cell lines and patient-derived organoids/xenografts. Therapeutic effects were tested in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion and were analyzed a postoperative cohort (n=40) treated with lenvatinib+PD-1.
Results HKDC1, upregulated in LR HCC, was transcriptionally activated by upstream stimulatory factor 1 (USF1) and promoted spermine synthase (SMS)-mediated polyamine rewiring. This impaired CD8+ T-cell metabolism, reversible by HKDC1 knockdown or SPD. SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib+aPD-1.
Conclusions A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and supports polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.
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Regulation of immune tolerance in hepatocellular carcinoma by liver diseases: a review Jinyi Li, Yuanda Liu Infectious Agents and Cancer.2026;[Epub] CrossRef
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer mortality worldwide. Its pathogenesis reflects a combination of tumour-intrinsic heterogeneity and a profoundly immunosuppressive tumour microenvironment. Growing evidence shows that tumours recapitulate developmental programs to establish an oncofetal ecosystem, characterised by the re-expression of foetal antigens and foetal-like stromal and immune subsets. These features drive immune evasion and shape therapeutic response, contributing to immunotherapy outcomes in clinic. This review outlines mechanistic insights into oncofetal reprogramming across tumour, stromal, and immune compartments and evaluates therapeutic strategies that target these dependencies. We highlight emerging vaccine platforms, cellular therapies, and biologics targeting oncofetal antigens, with particular emphasis on mRNA–lipid nanoparticle vaccines and their potential to induce robust, durable antitumour immunity. We further discuss rational combinatorial strategies that integrate vaccines with immune checkpoint inhibitors. Finally, we discuss how overcoming liver tolerance and antigenic heterogeneity will be essential for effective oncofetal-directed therapies. Collectively, targeting the oncofetal ecosystem through coordinated vaccine, cellular, and immunotherapeutic strategies offers a path toward more durable responses and broader immunotherapy benefits in HCC.
Background/Aims The GALAD (Gender, Age, Lens culinaris agglutinin-reactive alpha-fetoprotein [AFP-L3], alpha-fetoprotein [AFP], and des-γ-carboxy prothrombin) score, widely used for hepatocellular carcinoma (HCC) detection, was primarily derived from cohorts with advanced-stage tumors and elevated biomarker levels, potentially overestimating accuracy in early-stage disease. Furthermore, the lectin-based AFP-L3 assay has poor sensitivity at low AFP concentrations, limiting detection of small or AFP-negative tumors.
Methods We developed GAFAD, a multivariable model replacing AFP-L3 with fucosylated AFP percentage, quantified by a validated liquid chromatography–tandem mass spectrometry assay. The model was trained and tested using a hepatitis B virus (HBV)-related cohort (HCC n=235; non-HCC n=290), a diagnostically challenging set with substantial overlap in biomarker levels between HCC and non-HCC. Moreover, a final model (GAFAD) was validated in two independent cohorts (HCC n=210; non-HCC n=245), comprising HBV-, HCV-related and non-viral etiologies.
Results In the development cohort, GAFAD showed superior diagnostic performance to GALAD for distinguishing HCC from non-HCC, with a higher area under the receiver operating characteristic curve (AUC, 0.938 vs. 0.887; P<0.0001) and greater sensitivity (82% vs. 66%) and accuracy (86% vs. 79%) at 90% specificity. In the external validation cohort, GAFAD similarly outperformed GALAD, achieving a higher AUC (0.874 vs. 0.841, P<0.05), greater sensitivity (72% vs. 57%), and improved accuracy (82% vs. 75%) at 90% specificity. This superiority extended to early-stage, very-early-stage, and AFP-negative HCC.
Conclusions GAFAD provides a reliable and generalizable tool for early HCC detection across diverse etiologies, supporting its clinical applicability in surveillance and diagnosis.
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Background/Aims Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA.
Methods Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development.
Results DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression.
Conclusions Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.
Background/Aims Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy.
Methods We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues.
Results We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts.
Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.
Reply to correspondence on “MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation” Lei Wu, Yan Zheng Clinical and Molecular Hepatology.2026; 32(3): e445. CrossRef
Correspondence to letter to the editor on “Integrative multi-omics profiling identifies infiltrative hepatocellular carcinoma as an immunotherapy-resistant subtype with distinct molecular features” Won Suk Lee, Seonjeong Woo, Sohyun Hwang, Chan Kim, Hong Jae Chon Clinical and Molecular Hepatology.2026; 32(3): e411. CrossRef
Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and hepatocellular carcinoma (HCC). Advances in surgical techniques and immunosuppressive regimens have markedly improved early post-transplant survival. However, long-term outcomes remain compromised by HCC recurrence, chronic rejection, metabolic complications, and de novo malignancies. Recurrence of HCC after LT remains a major clinical challenge, with available prognostic models providing limited accuracy in risk stratification. Simultaneously, systemic therapies for unresectable HCC have rapidly advanced, particularly with immune checkpoint inhibitors (ICIs), providing new opportunities and unique challenges in transplant settings. With ICIs carrying a risk of acute and potentially fatal rejection and lacking controlled data on efficacy or safety in the post-transplant setting, tyrosine kinase inhibitors currently represent a standard option for post-transplant recurrence. Novel biomarkers, such as donor-derived cell-free DNA and the gut microbiome, are emerging as potential tools to refine risk stratification and guide immunosuppression. Furthermore, innovative immunotherapies, including oncolytic viruses and mRNA vaccines, are being explored as tumor-specific approaches. Collectively, these advances may reshape future management of LT recipients.
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Background/Aims Hepatocellular carcinoma (HCC) is characterized by profound transcriptomic dysregulation, yet the mechanism(s) by which DNA methylation is coordinated with chromatin modifications to regulate alternative splicing during tumorigenesis remains poorly understood.
Methods Using prospectively paired multi-omics data obtained from metabolic dysfunction-associated steatotic liver disease (MASLD)-HCC patients and coupled with a premalignant MASLD cohort, we have uncovered a previously unrecognized gene-regulatory axis centered on TACC3 isoform-switching.
Results In the non-tumoral context, the TACC3-201 isoform directly engages the histone acetyltransferase KAT2A to coordinate the regulation of NOTCH4 signaling. In HCC, this regulatory axis is disrupted whereby FOXM1 overrides DNMT1-mediated methylation, upregulating TACC3, and decoupling TACC3 from the KAT2A-associated NOTCH4 co-expression module. This rewiring is licensing tumor-specific cell-cycle progression and epigenetic plasticity. Thus, FOXM1 reshapes the TACC3-KAT2A interaction, while DNMT1 drives context-dependent DNA methylation, activating the CDK1-inhibitory kinase PKMYT1.
Conclusions We uncovered TACC3-KAT2A as an emerging regulatory axis caused by alternative splicing in HCC and propose FOXM1-driven TACC3 inhibition to synergistically disrupt mitotic fidelity and transcriptional regulation, potentially offering new therapeutic avenues for HCC with reduced toxicity to the normal liver.
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Alternative splicing regulates FGGY-derived neoantigen presentation and promotes immune evasion in metabolic-associated hepatocellular carcinoma Li Na Zhao, Jesper B. Andersen iScience.2026; 29(6): 115999. CrossRef
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Background/Aims Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood.
Methods Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort.
Results Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models.
Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.
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COLEC12high tumor-associated macrophages: A novel paracrine axis driving lenvatinib resistance in hepatocellular carcinoma: Editorial on “COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carc Ji Won Han Clinical and Molecular Hepatology.2026; 32(3): 1463. CrossRef
Background/Aims Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies.
Methods Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification.
Results Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo.
Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.
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Background/Aims Various expanded criteria (EC) for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) have been proposed to avoid the narrow nature of the Milan criteria (MC). To investigate which EC predicts more favorable outcomes in terms of overall survival (OS) and recurrence-free survival (RFS), we conducted a network meta-analysis (NMA).
Methods A database search was conducted on PubMed, Embase, and the Cochrane Library, to identify studies comparing OS and RFS between patients within the MC and those exceeding the MC but within the EC. Hazard ratios (HRs) were pooled using a random-effects NMA and validated in an in-house cohort of 1,008 LT recipients.
Results Among 22,466 articles identified, 35 studies with 45 pairwise comparisons were included in the NMA along with 8 different EC. The University of California San Francisco (HR, 1.43; 95% CI, 1.19–1.71), Up-to-Seven (HR, 1.50; 95% CI, 1.15–1.97), and Hangzhou criteria (HR, 1.69; 95% CI, 1.11–2.57) showed inferior OS to the MC. The MC ranked highest for both OS and RFS, followed by Metroticket 2.0 for OS and the Asan criteria for RFS. In the validation cohort, both Metroticket 2.0 and AFP model yielded more favorable HCC-specific mortality than other EC.
Conclusions Several EC, of which those of Metroticket 2.0 were the best, yielded comparable outcomes to the MC. AFP-based EC such as Metroticket 2.0 and AFP model appeared to be useful in both the NMA and the validation cohort, suggesting a potential role in identifying selected low-risk patients beyond the MC.
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Liver cancer is one of the deadliest malignancies, with increasing incidence worldwide. Recent advances in immunotherapy have expanded the options for systemic therapy against advanced hepatocellular carcinoma (HCC), but there are no biomarkers currently available to predict which patients will respond, leading to suboptimal patient selection strategies. Understanding of the genetic and immunologic features of HCC is accelerating rapidly through the use of single cell and spatial transcriptomic techniques. However, there is a need to translate insights gained through these new studies to improve treatment options and improve patient selection. In this review we summarize knowledge of the immunogenomics of HCC, emphasizing recent advances, and discuss progress toward clinical translation.
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Clin Mol Hepatol 2026;32(1):353-367. Published online December 1, 2025
Background/Aims Previous studies suggest that hypothyroidism is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and its histological severity, but clinical outcome data are largely lacking. We aimed to study the impact of hypothyroidism on liver-related events (LREs).
Methods Patients with MASLD were identified from a territory-wide registry in Hong Kong during 2000–2024. Thyroid status was determined using diagnosis codes and thyroid function tests. The primary outcome, LRE, was defined as a composite of hepatic decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death.
Results A total of 20,478 patients with MASLD were included in the final analysis (mean age 56.4±13.2 years; 43.9% male). At baseline, 18,178 (88.8%) patients were euthyroid, 598 (2.9%) were hyperthyroid, and 1,702 (8.3%) were hypothyroid. Compared with euthyroid patients, both hyperthyroidism and overt hypothyroidism were associated with cirrhosis. At a median follow-up of 4.8 years, 179 patients developed LREs, and 26 died from liver disease. Compared with patients with normal serum thyroid-stimulating hormone (TSH) levels of 0.4–4 mIU/L, those with subclinical (4–10 mIU/L; adjusted time-dependent cause-specific hazard ratio [aCSHR], 2.49; 95% CI, 1.51–4.13) and overt hypothyroidism (>10 mIU/L; aCSHR, 4.91; 95% CI, 1.56–15.47) had an increased risk of LREs. Time-dependent, but not baseline, TSH and thyroid status were associated with LRE risk.
Conclusions Subclinical and overt hypothyroidism are associated with an increased risk of LREs in a dose-dependent manner. The association with time-dependent but not baseline thyroid status underscores the importance of thyroid monitoring and suggests that correction of hypothyroidism may mitigate LRE risk.
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Hypertension and long-term adverse clinical outcomes in MASLD: Sensitivity analyses for unmeasured or uncontrolled confounding Guiying Gao, Xiuhong Wang, Ruizhe Huang, Jing Cao Journal of Hepatology.2026; 84(6): e209. CrossRef
Not just fat: muscle also matters in metabolic dysfunction-associated steatotic liver disease (MASLD) Xinyan Zong, Grace Lai-Hung Wong Hepatology International.2026; 20(3): 550. CrossRef
Dynamic Thyroid Function Assessment May Improve Risk Prediction in Metabolic Dysfunction—Associated Steatotic Liver Disease Patients Gabriela Brenta Clinical Thyroidology®.2026; 38(7): 240. CrossRef
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Won Suk Lee, Seonjeong Woo, Sung Hwan Lee, Gae Hoon Jo, Ilhwan Kim, Hyeyeong Kim, Chansik An, Sanghoon Jung, Gwangil Kim, Haeyoun Kang, Beodeul Kang, Jung Sun Kim, Ho Yeong Lim, Incheon Kang, Hannah Yang, So Jung Kong, Dahyeon Son, Dong Jun Shin, Woo Young Kwon, Da-Yeon Lee, Ju-Seog Lee, Junho Park, Youngsoo Kim, Sohyun Hwang, Chan Kim, Hong Jae Chon
Clin Mol Hepatol 2026;32(1):258-275. Published online October 27, 2025
Background/Aims Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).
Methods We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.
Results Infiltrative morphology, encompassing pure and mixed forms, was present in 42.7% of advanced HCC and associated with advanced disease features and compromised liver function. Patients with type IV infiltrative HCC showed lowest objective response rate (14.6%) and worst progression-free (median, 2.8 months) and overall survival (median, 7.1 months). Infiltrative morphology remained an independent predictor of poor outcomes after multivariable adjustment for confounders, including intrahepatic tumor extent. Genomic profiling revealed enriched TP53 and ATM loss-of-function mutations in type IV infiltrative HCC. Transcriptomic and proteomic analyses identified consistent activation of tumor proliferation, epithelial-mesenchymal transition, TGF-β signaling, and immunosuppressive pathways in type IV infiltrative HCC. Type IV infiltrative signature was significantly associated with poor survival across external datasets and retained independent prognostic value.
Conclusions Infiltrative HCC is a clinically aggressive and molecularly distinct subtype of advanced HCC. Morphological classification and type IV infiltrative signatures may guide risk stratification and therapeutic decision-making in advanced HCC treated with immunotherapy.
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