New insight for SS‑31 in treating diabetic cardiomyopathy: Activation of mitoGPX4 and alleviation of mitochondria‑dependent ferroptosis.

SS‑31 is a mitochondria‑targeting antioxidant that exhibits promising therapeutic potential for various diseases; however, its protective effect on diabetic cardiomyopathy (DCM) remains to be elucidated. At present, SS‑31 is considered not only to mitigate cardiolipin oxidative damage, but also to alleviate ferroptosis. The present study aimed to explore SS‑31 as a potential therapeutic strategy for improving DCM by alleviating mitochondria‑dependent ferroptosis. In vitro, H9C2 cells were exposed to 35 mM glucose for 24 h to induce high glucose damage, then were simultaneously treated with 10, 20 or 50 µM SS‑31. In addition, in vivo studies were conducted on diabeticC57BL/6J mice, which were induced to develop DCM over 4 weeks, followed by intraperitoneal injections with 2.5 mg/kg/day SS‑31 for a further 4 weeks. The elevation of serum lactate dehydrogenase and creatine kinase isoenzymes, the reduction of fractional shortening and ejection fraction, the rupture of myocardial fibers and the deposition of collagen indicated the establishment of the DCM mouse model. The results of the present study indicated that SS‑31 effectively alleviated these pathological changes and exhibited significant efficacy in ameliorating mitochondrial dysfunction, such as by promoting adenosine triphosphate generation, improving mitochondrial membrane potential and restoring the mitochondrial ultrastructure. Further experiments suggested that activation of the mitochondrial glutathione (mitoGSH)/mitochondrial glutathione peroxidase 4 (mitoGPX4) pathway and the elimination of mitochondrial ferrous ions may constitute the mechanisms by which SS‑31 treats DCM. Therefore, the present study revealed that mitochondria‑dependent ferroptosis could serve as a pathogenic mechanism of DCM and highlighted that the cardioprotective effects of SS‑31 against DCM involves activation of the mitoGSH/mitoGPX4 pathway. Due to the safety profile and cardiac protective effects of SS‑31, SS‑31 was considered a promising strategy for treating DCM.