MenSC-EV-derived HSPA5 activates the AKT/mTOR axis to suppress ferroptosis in Type 1 diabetes mellitus-associated ovarian dysfunction.

Type 1 diabetes mellitus (T1DM) is associated with ovarian dysfunction, including menstrual irregularities, impaired ovarian reserve, and premature reproductive aging, yet effective therapeutic strategies to safeguard ovarian function against metabolic stress remain limited. Mesenchymal stem cells (MSCs) have emerged as pivotal regulators of tissue homeostasis, with their paracrine effects largely mediated by extracellular vesicles (EVs). Here, we demonstrate that menstrual blood-derived endometrial stem cell-EVs (MenSC-EVs) alleviate streptozotocin (STZ)-induced ovarian dysfunction and inhibit granulosa cells (GCs) ferroptosis by delivering HSPA5. Mechanistically, EV-associated HSPA5 restored AKT/mTOR signaling and was accompanied by reduced BECN1 phosphorylation, thereby preserving the SLC7A11/GPX4-associated antioxidant pathway. We further show that BECN1 directly interacts with SLC7A11, linking BECN1 signaling to regulation of the system Xc-/GPX4 antioxidant axis. MenSC-EVs preserved this antioxidant pathway and reduced lipid peroxidation in injured GCs. Collectively, these findings identify an HSPA5-dependent anti-ferroptotic mechanism through which MenSC-EVs ameliorate T1DM-associated ovarian dysfunction, supporting their potential as an ovarian-protective strategy under diabetic conditions.