Irisin Protects Against Diabetic Cardiomyopathy by Suppressing Ferroptosis

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Abstract
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.
Funding Information
  • National Natural Science Foundation of China

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