Regulatory mechanisms of m⁶A methylation in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a complex heart condition marked by genetic mutations, myocardial dysfunction, and progressive heart failure. N6-methyladenosine (m⁶A) methylation, a key epigenetic modification, plays a crucial role in DCM by regulating gene expression in various pathologic processes, including cardiomyocyte death, inflammation, fibrosis, and mitochondrial dysfunction. m⁶A modifications influence cardiomyocyte survival by modulating apoptosis, necroptosis, ferroptosis, and autophagy-related genes, balancing cellular death and survival pathways. Additionally, m⁶A-driven regulation of inflammation and fibrosis contributes to immune microenvironment stability and extracellular matrix remodeling, affecting fibroblast activation and myocardial stiffness. Mitochondrial health, vital for cardiomyocyte energy demands, is also regulated by m⁶A methylation. Enzymes like methyltransferase-like (METTL) 3 and METTL14 promote mitophagy-related gene expression, while fat mass and obesity-associated protein modulates calcium homeostasis, mitigating oxidative stress and energy imbalances. Targeting m⁶A-related enzymes with small molecules, gene editing, or RNA interference (RNAi) offers potential for tailored DCM therapy. Emerging technologies, such as nanopore m⁶A-modified mRNA detection, reveal new insight into cardiomyocyte metabolism, suggesting novel therapeutic avenues. This review underscores m⁶A methylation as a pivotal epigenetic mechanism of DCM, providing a basis for advanced diagnosis and therapy.