Traditional Chinese Medicine Intervention Based on Metabolic-Epigenetic Axis: Mechanism and Treatment Strategy of Chronic Heart Failure.

Chronic heart failure [CHF] is a progressive clinical syndrome characterized by structural and functional impairment of the myocardium, in which energy metabolic remodeling plays a central role. Increasing evidence suggests that metabolic disturbances in CHF are not only a consequence of reduced cardiac output but also active regulators of epigenetic remodeling, thereby contributing to disease progression. Key metabolites, including α-ketoglutarate, acetyl-CoA, NAD+, S-adenosylmethionine, succinate, and 2-hydroxyglutarate, influence the activity of DNA methyltransferases, histone-modifying enzymes, and other chromatin regulators, thereby linking metabolic status to transcriptional control. Through these mechanisms, metabolic abnormalities promote persistent activation of pathological gene programs associated with cardiomyocyte hypertrophy, fibrosis, inflammation, apoptosis, and mitochondrial dysfunction, forming a self-reinforcing metabolic-epigenetic feedback loop in CHF. Although current guideline-directed medical therapies improve symptoms and clinical outcomes, they do not directly target this metabolic-epigenetic axis. Traditional Chinese medicine (TCM), including bioactive compounds, herbal formulas, patent medicines, and injections, has demonstrated potential in preclinical studies to modulate myocardial energy metabolism, improve mitochondrial function, and influence epigenetic regulators such as SIRT1, AMPK, and TET/JmjC-dependent pathways. However, most available evidence is derived from experimental models, and causal relationships between metabolite regulation, epigenetic remodeling, and cardiac functional improvement remain insufficiently validated. This review summarizes current knowledge on metabolite-driven epigenetic regulation in CHF and evaluates emerging evidence on the role of TCM in modulating this network. We also critically discuss key limitations, including reliance on non-clinical models, incomplete pharmacokinetic understanding, and insufficient causal validation. Finally, we propose future directions based on multi-omics integration, single-cell and spatial technologies, and systems biology approaches to facilitate mechanistic clarification and translational development of metabolism-targeted strategies for CHF.