Ketamine improves ovarian function and oocyte quality in CORT-induced depression mouse model by ferroptosis pathway

Abstract Depression is a common psychiatric disorder, with a higher prevalence in women than in men, and has been increasingly associated with disturbances in female reproductive health. In particular, depressive conditions may impair ovarian function and compromise oocyte quality, thereby contributing to reproductive disorders. Ketamine is a clinically effective antidepressant. However, its potential role in improving depression-induced female reproductive disorders remains unclear. In the present study, a corticosterone (CORT)-induced mouse model of depression was used to evaluate whether ketamine could ameliorate ovarian dysfunction and oocyte impairment. Ketamine treatment significantly improved depressive-like behaviors and partially reversed abnormalities in ovarian function and oocyte quality. Metabolomics and single-cell transcriptomics analyses suggested that ketamine may enhance oocyte quality in depressive mice through the regulation of ferroptosis. Our findings confirmed that ketamine ameliorated alterations in ROS, Fe 2+ , glutathione (GSH), and lipid peroxidation levels in oocytes, reduced ovarian mitochondrial abnormalities, and regulated the ferroptosis-related proteins GPX4, FTH1, and FTL in ovarian tissues. In conclusion, ketamine alleviates depression-associated ovarian dysfunction and oocyte impairment, potentially through modulation of ferroptotic signaling, offering new insights linking mental disorders to female reproductive health.