HucMSC-derived exosomes alleviate chemotherapy-induced premature ovarian insufficiency via SMURF1-mediated inhibition of ferroptosis in ovarian granulosa cells

BACKGROUND: Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exo) have shown great therapeutic promise in the treatment of primary ovarian insufficiency (POI). Ferroptosis, a distinct form of cell death, has been associated with the pathogenesis of POI. However, whether HucMSC-Exo can mitigate POI by modulating ferroptosis remains unknown. METHODS: In a CTX-induced POI mouse model, HucMSC-Exo was administered. Ovarian function was assessed by monitoring the estrous cycle, hormone levels, ovarian index, fertility rate, and ovarian morphology. The molecular mechanisms underlying injury and repair were investigated through HucMSC-Exo tracing, immunohistochemical staining, western blot, and real-time polymerase chain reaction (PCR). RESULTS: HucMSC-Exo restored hormonal balance, preserved ovarian reserve, and reduced follicular atresia and developmental defects in a cyclophosphamide (CTX)-induced POI mouse model. Furthermore, HucMSC-Exo attenuated Fe²⁺ accumulation, oxidative stress, and ferroptosis in the granulosa cells (GCs) of atretic follicles in ovaries with POI. In vitro assays also demonstrated that HucMSC-Exo attenuated CTX-induced ferroptosis in GCs by alleviating Fe²-dependent oxidative damage. Interestingly, hucMSC-Exo specifically suppressed the CTX-induced upregulation of heme oxygenase-1 (HO-1), a key regulator of iron homeostasis, at the translational level. This suggests that post-translational modifications may play a regulatory role in HO-1 expression and iron homeostasis. Mechanistic studies revealed that HucMSC-Exo delivers SMURF1, an E3 ubiquitin ligase that promotes HO-1 degradation, thereby restoring iron homeostasis and inhibiting ferroptosis in GCs. Furthermore, HO-1 knockdown enhanced the protective effects of HucMSC-Exo against CTX-induced ferroptosis and cytotoxicity in GCs. CONCLUSIONS: accumulation and lipid peroxidation, thereby preventing ferroptosis in GCs and ameliorating chemotherapy-induced POI.