Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate ovarian aging by inhibiting ferroptosis

Ovarian aging is characterized by a decline in oocyte quantity and quality, often driven by oxidative stress and cellular damage. Human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-Exos) have emerged as a potent cell-free therapy for regenerative medicine. In this study, Female mice with early ovarian aging (31-33 weeks; n = 8 per group) received 10 intraperitoneal injections of hUC-MSC-Exos (240 µL/dose, 6.5 × 10¹⁰ particles/mL) over two weeks. Ovarian function, follicular development, DNA damage, and ferroptosis-related markers were evaluated. hUC-MSC-Exo treatment significantly increased the number of primary and antral follicles without a significant change in primordial follicle counts. Exosome administration reduced genomic stress, evidenced by decreased TUNEL intensity, and improved oocyte yield and mitochondrial metabolic state. Mechanistically, hUC-MSC-Exos promoted the nuclear translocation of NRF2, a master antioxidant regulator. This activation was accompanied by the suppression of ferroptosis, indicated by up-regulation of GPX4 and SLC7A11 and down-regulation of 4-HNE and ACSL4. Furthermore, exosome treatment restored ovarian functional markers (AMH, BMP15) and steroidogenic proteins (CYP11A1, 3β-HSD, StAR). These findings suggest that hUC-MSC-Exos mitigate age-related ovarian dysfunction by modulating NRF2-mediated antioxidant defenses and inhibiting ferroptosis, offering a promising candidate that warrants validation with functional reproductive endpoints.