HuMSCs-derived exosomes alleviate premature ovarian insufficiency by enhancing SIRT3-mediated mitochondrial function in theca-interstitial cells

Premature ovarian insufficiency (POI) is a reproductive disorder lacking effective treatment options. This study explores the therapeutic potential of exosomes derived from human umbilical cord mesenchymal stem cells (HuMSCs-Exos) in restoring ovarian function in a cyclophosphamide (CTX)-induced POI mouse model. HuMSCs-Exos treatment significantly improved ovarian structure, restored follicular development, and normalized key hormone levels, enhancing estrous cycle regularity and fertility in POI mice. Mechanistic investigations revealed that HuMSCs-Exos promote SIRT3 expression, which modulates mitochondrial dynamics and reduces apoptosis in ovarian theca-interstitial cells (TICs). Furthermore, HuMSCs-Exos restored mitochondrial membrane potential and enhanced testosterone synthesis in TICs under CTX-induced stress, effects that were mitigated by the SIRT3 inhibitor 3-TYP, highlighting SIRT3 as a critical mediator. These findings indicate that HuMSCs-Exos support ovarian recovery, with effects consistent with the activation of SIRT3-mediated mitochondrial stabilization pathways in TICs, suggesting a promising therapeutic approach for POI.