FTO-Mediated Mitigation of Ferroptosis Occurs in an ACSL4-Dependent Manner in Diabetic Cardiomyopathy.

Considering the global prevalence of diabetes, diabetic cardiomyopathy (DCM), as a significant diabetes complication, remains a major human challenge; while previous studies have identified ferroptosis as an important underlying mechanism, the unclear regulatory mechanisms hamper the development of therapy for DCM. In this study, we reveal that the expression of the fat mass and obesity-associated protein (FTO) is downregulated in DCM. Overexpression of FTO was found to enhance cardiac function by inhibiting ferroptosis. Mechanistically, acyl - CoA synthetase long - chain family 4 (ACSL4), a key positive mediator of ferroptosis, was identified as a direct target of FTO. The ameliorative effect of FTO was contingent upon the inhibition of ACSL4, and FTO-mediated mitigation of ferroptosis occurs in an ACSL4-dependent manner in DCM. Furthermore, we demonstrate that nicotinamide mononucleotide and sulforaphane can synergistically suppress ferroptosis by targeting distinct pathways, thereby better alleviating cardiac dysfunction. Collectively, our findings uncover an FTO - ACSL4 regulatory axis that plays a crucial role in the pathogenesis of DCM, offering valuable insights for the development of therapeutic strategies against DCM.