We reviewed the critical role of fat mass and obesity-associated protein (FTO), an m6A demethylase, in regulating numerous diseases, including heart failure. It was evidenced that the FTO's involvement in m6A modification significantly affects cardiac functions, as revealed through in vitro and in vivo studies, elucidating that the alterations in m6A methylation, which FTO mediates, would influence myocardial cell functionality in humans and model organisms. Beyond heart failure, FTO's regulatory capacity extends to conditions such as asthma, hyperlipidemia, insulin resistance, and hypertension by modulating m6A levels, thereby affecting gene expression linked to critical heart health and disease pathways. Exploring FTO's structure through crystallography uncovers potential sites for targeted intervention. At the same time, genetic analyses reveal SNPs associated with an increased heart failure risk, suggesting a genetic predisposition that could guide personalized medicine. Targeting FTO for therapeutic intervention could regulate gene expression beneficial in heart failure and other diseases. This comprehensive examination of FTO's influence on m6A methylation and cardiac disease mechanisms is a foundational reference for future research. The findings suggest comprehensive investigations to validate therapeutic candidates targeting to combat myocardial infraction and associated heart-failure in the global population.

Keywords: FTO gene, ULK1, KLF5, m6A demethylase, Heart failure