The epigenetic landscape of hepatocellular carcinoma: from molecular mechanisms to early detection biomarkers and precision therapy.

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of global cancer mortality due to late diagnosis, molecular heterogeneity, and therapeutic resistance. Emerging evidence highlights that epigenetic and epitranscriptomic dysregulations drive hepatocarcinogenesis by altering gene expression programs without changing the underlying DNA sequence. Aberrant DNA methylation, histone modifications, chromatin remodeling, non-coding RNA networks, and N6-methyladenosine (m6A) RNA modifications collectively orchestrate HCC initiation, progression, metastasis, immune evasion, and metabolic reprogramming. Recent breakthroughs in next-generation sequencing, liquid biopsy, and multi-omics profiling have accelerated the identification of robust epigenetic biomarkers for early detection, prognosis, and therapeutic monitoring. Concurrently, epigenetic-targeted therapies, including DNA methyltransferase, histone deacetylase, EZH2, and BET inhibitors, offer promising preclinical and clinical opportunities for precision oncology, particularly through rational combination strategies to overcome drug resistance. This review provides a comprehensive synthesis of the molecular mechanisms governing epigenetic and epitranscriptomic alterations in HCC. We highlight their translational potential in clinical practice and critically discuss current challenges, emerging technologies, and future perspectives for successful clinical implementation.