The Role of Histone Methylation in Heart Failure: Epigenetic Mechanisms and Therapeutic Perspectives

Yingli Zhou,1,2,* Zhaoyang Dong,2,3,* Yuxuan Gao,3,* Keying Xiao,3 Qinglan Huang,1 Qianqian Cao,3 Xiaoyu Wang,3 Yuxian Duan,3 Zhihua Guo,1,2 Jiaming Wei2,3 1First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410007, People’s Republic of China; 2Hunan Key Laboratory of Colleges and Universities of Intelligent TCM Diagnosis and Preventive Treatment of Chronic Diseases, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 3School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Guo, First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410007, People’s Republic of China, Email [email protected] Jiaming Wei, School of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China, Email [email protected]: Heart failure (HF) represents the terminal stage of various cardiovascular diseases, and its prevalence continues to rise while current therapeutic approaches remain insufficient to reverse disease progression. Epigenetic regulation, with a particular focus on histone methylation, has gained increasing attention for its involvement in the initiation and advancement of HF. Histone methylation is a reversible post-translational modification controlled by histone methyltransferases and demethylases, and it participates in essential biological processes such as gene expression regulation, cell cycle, apoptosis, and metabolic reprogramming. This review systematically summarizes the multifaceted roles of histone methylation in HF, including the specific functions in cardiac regeneration, hypertrophy, fibrosis, apoptosis, metabolic remodeling, and inflammation. The review also highlights the promising effects of inhibitors that target histone methylation enzymes in animal studies, including anti-hypertrophic, anti-fibrotic, and cardioprotective properties, suggesting significant potential for clinical translation. Keywords: histone modification, histone methyltransferase, histone demethylase, heart failure, mechanism