Hepatocellular carcinoma (HCC) is a highly lethal cancer in which epigenetic dysregulation plays a key role in tumor development and progression. Among epigenetic mechanisms, histone methylation regulates chromatin structure and gene transcription and influences multiple aspects of HCC biology, including tumor proliferation, metastasis, immune modulation, cancer stemness, and therapeutic resistance. In this review, we summarize recent advances in understanding the roles of histone methyltransferases in HCC, focusing on their involvement in tumor proliferation, metastasis, immune regulation, drug resistance, and cancer stem cell maintenance. We also discuss their clinical relevance as potential diagnostic and prognostic biomarkers and highlight emerging therapeutic strategies targeting histone methylation pathways. Collectively, these findings suggest that histone methyltransferases represent promising targets for developing novel epigenetic-based diagnostic and therapeutic approaches for HCC.
