Ulinastatin protects against cisplatin-induced ovarian damage via Nrf2/Keap1 pathway

The administration of chemotherapeutic agents such as cisplatin frequently results in ovarian damage and premature ovarian failure (POF), severely compromising fertility and quality of life in young women. This study aimed to investigate the protective effects of ulinastatin, a compound with anti-inflammatory and antioxidant properties, against cisplatin-induced ovarian injury and to elucidate the underlying mechanisms through the Nrf2/Keap1 pathway. In vivo and in vitro models were established using cisplatin-treated rats and ovarian granulosa cells. Experimental results demonstrated that ulinastatin significantly alleviated cisplatin-induced ovarian structural damage, reduced follicular atresia, and inhibited ovarian fibrosis and inflammation. Furthermore, ulinastatin restored serum hormone levels (FSH, E2, AMH), mitigated oxidative stress by reducing ROS and MDA levels while increasing SOD and GSH levels, and suppressed Apoptosis by downregulating cleaved-caspase-3 and Bax while upregulating Bcl-2. Most importantly, ulinastatin activated the Nrf2/Keap1 pathway. Keap1 silencing enhanced the protective effects of ulinastatin, whereas Keap1 overexpression attenuated these effects, confirming that the Nrf2/Keap1 pathway is the key mediator of ulinastatin's protective role in the ovary. These findings underscore the dual function of ulinastatin in repairing cisplatin-induced ovarian damage and provide a promising therapeutic strategy for preserving fertility in female Cancer patients undergoing chemotherapy.

Cisplatin; Ovarian damage; Oxidative stress; Ulinastatin.