Irisin Protects Against Diabetic Cardiomyopathy by Suppressing Ferroptosis.

Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, particularly those with type 2 diabetes. Ferroptosis is closely linked to the onset and progression of various cardiovascular diseases. Irisin, a myokine produced by exercising skeletal muscle, has been shown to mitigate DCM. However, whether irisin alleviates type 2 DCM by inhibiting ferroptosis remains unclear. This study aimed to determine whether irisin prevents DCM by suppressing ferroptosis. First, ferroptosis was examined in palmitic acid (PA)-induced cardiomyocytes. Next, the effects of irisin on PA-induced cardiomyocytes were evaluated. Finally, the molecular mechanisms underlying irisin's protective effects against DCM were investigated. Ferroptosis was identified in an In Vitro model of type 2 DCM induced by PA. Irisin reduced PA-induced ferroptosis and alleviated myocardial injury, as indicated by decreased reactive oxygen species (ROS) production, Fe²⁺ content, and malondialdehyde (MDA) levels, along with increased glutathione (GSH) levels and mitochondrial membrane potential (MMP). Further analysis suggested that irisin does not mitigate PA-induced ferroptosis through iron metabolism or lipid peroxidation pathways but instead inhibits ferroptosis via the System Xc-/GSH/GPX4 axis. Additionally, irisin reduced the secretion of inflammatory cytokines, including IL-1β and IL-6. These findings indicate that irisin prevents the progression of DCM by suppressing ferroptosis through the System Xc-/GSH/GPX4 axis and reducing inflammation.