MSC-EV-transmitted HSPA8 alleviates cisplatin-induced ovotoxicity by regulating the MGARP/PRDX2 axis

Cisplatin (Cis) is among the most widely employed antitumour agents, although its clinical application is limited by self-induced multiple-organ toxicity. Previous studies have demonstrated the essential role of mitochondrial injury in the pathogenesis of Cis-induced ovotoxicity. Notably, mesenchymal stem cell-extracellular vesicles (MSC-EVs), potential cell-free therapeutic agents, exhibit pronounced advantages for the treatment of ovarian dysfunction. However, little is known about which core component contained in MSC-EVs plays a major role in repairing Cis-induced ovarian damage, and further, the potential mechanisms underlying the repair of mitochondrial damage remain unclear. Herein, our study first verified that MSC-EVs effectively ameliorate Cis-induced ovarian dysfunction by upregulating the level of mitochondrion-localized glutamic acid-rich protein (MGARP), after which MGARP repairs mitochondrial damage and inhibits cellular ROS production by combining with and suppressing the degradation of peroxiredoxin 2 (PRDX2) in granulosa cells (GCs). More importantly, our study further showed that heat shock protein family A member 8 (HSPA8) is indispensable for MenSC-EV-mediated improvement of Cis-induced ovotoxicity. This investigation provides novel insights into the molecular mechanisms by which MSCs alleviate Cis-induced ovotoxicity through improving mitochondrial dysfunction.