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

In brief: Ovarian aging and the resulting decline in oocyte quality remain significant challenges for female reproductive health and fertility. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes can partially improve ovarian aging-associated phenotypes by activating NRF2-mediated antioxidant defenses and inhibiting ferroptosis, offering a promising cell-free therapeutic strategy. Abstract: 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 2 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 terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) intensity, and improved oocyte yield and mitochondrial metabolic state. Mechanistically, hUC-MSC-Exos promoted the nuclear translocation of Nuclear factor erythroid 2 related factor 2 (NRF2), a master antioxidant regulator. This activation was accompanied by the suppression of ferroptosis, indicated by upregulation of GPX4 and SLC7A11 and downregulation of 4-HNE and ACSL4. Furthermore, exosome treatment restored ovarian functional markers (anti-Müllerian hormone [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.