Metabolic-epigenetic interactions in heart failure: Current understanding and future directions

Heart failure remains a major global health concern characterized by complex pathophysiological processes and significant clinical challenges. While the distinct roles of metabolic and epigenetic dysregulation in heart failure are increasingly recognized, their intricate interplay remains a critical, yet underexplored, aspect of its pathophysiology. This review provides a comprehensive examination of this metabolic-epigenetic crosstalk, exploring how metabolic changes, such as impaired fatty acid oxidation, increased glycolysis, and mitochondrial dysfunction, alter epigenetic landscapes through shifts in intermediary metabolites including acetyl-CoA, NAD+, and α-ketoglutarate. Conversely, epigenetic dysregulation in the forms of DNA methylation and histone acetylation, for example, contribute to metabolic maladaptation through suppression of critical genes for oxidative phosphorylation and mitochondrial biogenesis. By providing an integrative framework linking metabolic and epigenetic circuits, this review aims to enhance our understanding of this pervasive condition and highlight emerging therapeutic targets within these networks.