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Abstract Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death. The accumulation of genetic and epigenetic changes is closely related to the occurrence and development of HCC. Enhancer of zeste homolog 2 (EZH2, a histone methyltransferase) is suggested to be one of the principal factors that mediates oncogenesis by acting as a driver of epigenetic alternation. Recent studies show that EZH2 is widely involved in proliferation and metastasis of HCC cells. In this review, the functions of EZH2 in HCC progression, the role of EZH2 in tumor immunity and the application of EZH2-related inhibitors in HCC therapy are summarized.