Empagliflozin Ameliorates Diabetic Cardiomyopathy by Inhibiting Ferroptosis via SIRT3: Mechanisms and Therapeutic Implications
Abstract
Empagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor, has garnered attention for its cardiovascular benefits beyond glycemic control. Ferroptosis, a novel form of regulated cell death, contributes to the pathogenesis of diabetic cardiomyopathy (DCM). However, whether EMPA mitigates DCM by suppressing ferroptosis remains unclear. Here, Type 2 diabetic db/db mice were used to establish a DCM model and treated with EMPA (10 mg/kg/day) for 12 weeks. EMPA significantly improved cardiac function, reduced myocardial fibrosis, and attenuated ferroptosis, concomitant with upregulated silent information regulator 3 (SIRT3) expression. In the rat cardiomyocytes (H9c2 cells) exposed to high glucose and palmitic acid, EMPA treatment or SIRT3 overexpression alleviated oxidative stress, mitochondrial dysfunction, and ferroptosis. Mechanistically, molecular docking, molecular dynamics simulation, cellular thermal shift assay and drug affinity responsive target stability assay confirmed that SIRT3 is the drug target of EMPA, stabilizing its protein levels and reducing acetylated p53 expression. Notably, SIRT3 silencing abolished EMPA's beneficial effects on oxidative stress and ferroptosis. Our findings demonstrate that EMPA exerts cardioprotective effects by inhibiting oxidative stress and ferroptosis in cardiomyocytes, which is mediated by SIRT3. This study provides novel insights into the mechanisms underlying EMPA's therapeutic effects in DCM.
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