EZH2: From Oncogenic Driver to Therapeutic Target for Overcoming Drug Resistance in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to the high prevalence of drug resistance. The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2), a core component of the Polycomb Repressive Complex 2, is frequently overexpressed in HCC and drives of drug resistance. This review delineates the multifaceted mechanisms by which EZH2 promotes resistance to chemotherapy, targeted therapy, and immunotherapy. We detail how EZH2 orchestrates pro-survival pathways by modulating cell cycle checkpoints, inhibiting apoptosis, enhancing DNA repair, and fostering an immunosuppressive tumor microenvironment. Furthermore, we evaluate the current landscape of EZH2 inhibitors, from clinically approved agents to novel therapeutic modalities like PROTACs, and discuss their potential to re-sensitize HCC to treatment. Finally, we outline future research directions, emphasizing combination strategies and biomarker development, to advance EZH2-targeting therapies for HCC.