DHCR7 promotes granulosa cells ferroptosis and represents a potential therapeutic target in premature ovarian insufficiency

Premature Ovarian Insufficiency (POI) is characterized by declining ovarian function before the age of 40, which affects female fertility. Granulosa cells (GCs) are essential for follicular development and ovarian function, and their dysfunction is closely involved in the pathogenesis of POI. In this study, transcriptomic data of GCs from POI patients and controls were analyzed using weighted Gene Co-expression Network Analysis (WGCNA), differential expressed analysis, Protein-Protein Interaction (PPI) network, and receiver operating characteristic (ROC) analysis to identify key genes associated with POI. A cisplatin-induced POI-like rat model was established for in vivo validation and mechanistic exploration. In vitro, human GCs were treated with cisplatin plus the Ferroptosis inhibitor deferoxamine (DFO), cisplatin plus small interfering RNA. Overexpression lentiviral model was used to further assess the role of candidate gene in Ferroptosis. We found that 7-dehydrocholesterol reductase (DHCR7) as a key gene associated with POI. In the cisplatin-induced POI-like rat model, DHCR7 expression was significantly upregulated and was accompanied by enhanced Ferroptosis and decreased GCs proliferation. Similarly, in human GCs, cisplatin treatment enhanced DHCR7 expression and promoted Ferroptosis. DFO treatment or DHCR7 knockdown attenuated Ferroptosis and rescued the survival of GCs. In contrast, DHCR7 overexpression aggravated Ferroptosis. This study suggests that DHCR7 promotes GCs Ferroptosis and participates in the pathogenesis of POI, indicating that DHCR7 may represent a potential therapeutic target for POI.