Dual action of SS31 via NRF2/HO-1: countering oxidative stress and metabolic dysfunction in ovarian aging

The global trend of delayed childbearing underscores age-related fertility decline as a critical health issue, driven primarily by the loss of ovarian follicles. Mitochondrial dysfunction and oxidative stress are key pathological factors in this process. SS31, a mitochondria-targeting antioxidant peptide, holds potential for mitigating reproductive aging, though its precise mechanisms in ovarian aging require further elucidation. This preclinical study utilized a naturally aged (10-month-old) female ICR mouse model and a D-galactose-induced senescence model in human KGN granulosa cells. We investigated the protective effects and mechanism of action of SS31 on the ovarian follicle unit. SS31 specifically localized to granulosa cell mitochondria. Treatment alleviated oxidative damage-induced apoptosis, improved mitochondrial function (including membrane potential and ATP production), and ameliorated senescence-associated impairment of the granulosa cell-oocyte unit. Mechanistically, SS31 enhanced cellular antioxidant capacity by activating the NRF2/HO-1 signaling pathway. This study demonstrates that SS31 preserves ovarian function by improving mitochondrial performance and redox homeostasis via the NRF2/HO-1 axis. These findings provide a solid theoretical and experimental foundation for the potential application of SS31 in delaying ovarian aging and treating related reproductive disorders, such as premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS), highlighting its significant translational value.