Histone Methylation: A Pivotal Epigenetic Driver of the Malignant Transformation of MASLD-HCC

Hepatocellular carcinoma (HCC) is characterized by high invasiveness and drug resistance, resulting in a generally poor prognosis for patients. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and its advanced form, Metabolic Dysfunction-Associated Steatohepatitis (MASH), are important precancerous lesions of HCC. Interventions during the critical precancerous stage before the occurrence of HCC have been recognized as a core strategy to improve prognosis. However, the key mechanisms driving the malignant transformation of MASLD/MASH to HCC remain incompletely elucidated. Among the multifaceted landscape of epigenetic alterations, histone methylation constitutes a dynamic and reversible regulatory layer uniquely positioned to couple metabolic stress with aberrant gene expression. Precisely governed by "writers", "erasers", and "readers", this modification serves as a crucial epigenetic checkpoint in the transition from benign steatosis to malignancy. A central unanswered question is which epigenetic sensors translate the metabolic milieu of MASLD/MASH into stable transcriptional reprogramming, and specifically how histone methylation dynamics govern the transition from reversible steatosis to irreversible malignancy. Increasing evidence suggests that abnormal histone methylation modifications are not only closely associated with the occurrence and development of HCC but may also dominate the transformation process from MASLD/MASH to early HCC, making them highly promising predictive biomarkers and therapeutic targets. This review summarises the molecular mechanisms of histone methylation modifications in the malignant transformation and progression of MASLD/MASH to HCC, to provide new epigenetic insights and potential targets for early intervention and treatment of HCC.