The epigenetic basis of hepatocellular carcinoma - mechanismsand potential directions for biomarkers and therapeutics

Sep 24, 2026

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Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, with diagnosis often delayed and treatments for intermediate-to-advanced disease limited by resistance and poor survival gains. A comprehensive molecular view is needed to improve tumor characterization and guide targeting. The epigenetic landscape of HCC includes global DNA hypomethylation and hypermethylation, histone-driven chromatin accessibility changes, genome-wide chromatin loop rearrangements, and RNA regulation via microRNAs and RNA modifications. Etiology-specific epigenetic aberrancies in viral hepatitis and MASLD support biomarker and epigenetic therapy development, including integration with immunotherapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction

Global epidemiology and clinical burden

Limitations of early detection

Current treatment landscape and unmet needs

British Journal of Cancer [www.nature.com/bjc](www.nature.com/bjc) REVIEW ARTICLE OPEN Genetics and Genomics The epigenetic basis of hepatocellular carcinoma – mechanismsand potential directions for biomarkers and therapeutics Hong-Yi Lin 1 ✉ , Ah-Jung Jeon2, Kaina Chen3, Chang Jie Mick Lee1,4, Lingyan Wu5, Shay-Lee Chong5, Chukwuemeka George Anene-Nzelu6, Roger Sik-Yin Foo 1,4,7,10 and Pierce Kah-Hoe Chow 5,8,9,10 ✉ © The Author(s) 2025 | | Hepatocellular carcinoma (HCC) is the sixth leading cancer worldwide and has complex pathogenesis due to its heterogeneity, along with poor prognoses. Diagnosis is often late as current screening methods have limited sensitivity for early HCC. Moreover, current treatment regimens for intermediate-to-advanced HCC have high resistance rates, no robust predictive biomarkers, and limited survival beneﬁts. A deeper understanding of the molecular biology of HCC may enhance tumor characterization and targeting of key carcinogenic signatures. The epigenetic landscape of HCC includes complex hallmarks of 1) global DNA hypomethylation of oncogenes and hypermethylation of tumor suppressors; 2) histone modiﬁcations, altering chromatin accessibility to upregulate oncogene expression, and/or suppress tumor suppressor gene expression; 3) genome-wide rearrangement of chromatin loops facilitating distal enhancer-promoter oncogenic interactions; and 4) RNA regulation via translational repression by microRNAs (miRNAs) and RNA modiﬁcations. Additionally, it is useful to consider etiology-speciﬁc epigenetic aberrancies, especially in viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), which are the main risk factors of HCC. This article comprehensively explores the epigenetic signatures in HCC, highlighting their potential as biomarkers and therapeutic targets. Additionally, we examine how etiology-speciﬁc epigenetic patterns and the integration of | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | epigenetic therapies with immunotherapy could advance personalized HCC treatment strategies. | | | | | British Journal of Cancer (2025) 132:869–887; [https://doi.org/10.1038/s41416-025-02969-8](https://doi.org/10.1038/s41416-025-02969-8) | | | | | | INTRODUCTION Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, the sixth most commonly diagnosed cancer, and the third leading cause of cancer death worldwide [1] . The incidence and mortality of HCC are projected to grow by more than 50% over the next two decades if global rates remain unchanged [1] . The early detection of HCC is presently suboptimal. The prevailing protocol for high-risk patients typically includes biannual abdominal ultrasounds supplemented by serum alphafetoprotein (AFP) testing [2] . However, the sensitivity for detecting early-stage HCC is only 47% with ultrasound alone, improving modestly to 63% when combined with AFP measurements [3] . This underscores the critical need for more precise diagnostic biomarkers to detect early-stage HCC reliably. Furthermore, HCC remains a formidable clinical challenge, with a dismal 5-year survival rate of just 18% . For advanced HCC, curative options are no longer feasible. Systemic cytotoxic chemotherapy has proven largely ineffective due to the dual burden of tumor progression and underlying chronic liver disease, which predisposes patients to hepatotoxicity and myelotoxicity [4] . Recent advances in systemic therapies have offered some hope. The combination of the programmed cell death-ligand 1 (PD-L1) inhibitor atezolizumab and the vascular endothelial growth factor A (VEGFA) inhibitor bevacizumab (atezo-bev) has become a recommended ﬁrst-line therapy for advanced HCC, alongside the dual checkpoint inhibitor combination of durvalumab and tremelimumab (durva-treme) [5] . These therapies marked a step forward in HCC manage

FAQs

Why is early detection of hepatocellular carcinoma difficult with current screening methods?

Early detection is limited because ultrasound alone has relatively low sensitivity, improving only modestly when combined with serum AFP testing.

What are the key epigenetic mechanisms implicated in hepatocellular carcinoma?

The document highlights global DNA methylation changes, histone modifications that alter chromatin accessibility, chromatin loop rearrangements affecting enhancer-promoter interactions, and RNA regulation through microRNAs and RNA modifications.

How might epigenetic insights improve treatment strategies for HCC?

By identifying epigenetic signatures as potential biomarkers and therapeutic targets, including etiology-specific patterns that could support more personalized treatment, potentially in combination with immunotherapy.

Sep 24, 2026

Uploaded by Rizky