Mitochondria-targeted peptide elamipretide alleviates cisplatin-induced ovarian failure by activating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

Background: Premature ovarian failure (POF) is a complex endocrine disorder that severely impairs female fertility. Cisplatin, a commonly used chemotherapeutic agent, has been identified as a major risk factor for POF in young women. This study aimed to investigate the protective effects and underlying mechanisms of the mitochondria-targeted peptide elamipretide (SS31) in a cisplatin-induced mouse model of POF. Methods: POF was established via intraperitoneal cisplatin (2 mg/kg, 7 days), followed by SS31 treatment (10 mg/kg, 3 weeks). Results: SS31 treatment significantly alleviated cisplatin-induced ovarian damage and reversed key pathological features of POF. Mice treated with SS31 exhibited more rapid recovery in body weight, increased ovarian size and weight, improved ovarian morphology, and a significantly higher number of follicles at various developmental stages compared to the model group. SS31 also normalized serum hormone levels, reduced oxidative stress, restored mitochondrial membrane potential, and improved mitochondrial morphology in oocytes and granulosa cells. Mechanistically, SS31 activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in ovarian tissues. Conclusion: The mitochondria-targeted peptide SS31 effectively ameliorates cisplatin-induced POF in mice by enhancing antioxidant defenses and preserving mitochondrial function. These findings suggest that SS31 is a promising therapeutic candidate for the clinical management of POF and provide new insights into antioxidant-based interventions.