Icaritin improves pregnancy outcomes in endometriosis by inhibiting ovarian granulosa cell senescence

BACKGROUND: Endometriosis (EMS) is an oestrogen-dependent chronic inflammatory disease that primarily manifests as chronic pelvic pain and infertility. EMS-associated infertility is closely linked to diminished ovarian function and oocyte quality, with the aberrant function of granulosa cells (GCs). Cellular senescence has a nonnegligible effect on female fertility. GCs in EMS patients may undergo senescence, subsequently compromising their nutritional support to oocytes and impairing ovarian function, ultimately contributing to infertility. Icaritin (Ica) possesses various biological activities including anti-tumour, anti-inflammatory, anti-oxidation and anti-aging. METHODS: Follicular fluid (FF) was collected from normal control females and EMS patients. GCs were extracted from FF for RNA sequencing and bioinformatic analysis. NADH: ubiquinone oxidoreductase core subunit S8 (NDUFS8)-knockdown KGN cells were established using shRNA-mediated lentiviral transduction. Pro-oxidants and oxidation scavengers were employed to modulate reactive oxygen species (ROS) levels. Network pharmacology was employed to analyse potential mechanisms of Ica in treating EMS. Ica was employed to intervene EMS-FF-treated KGN cells and EMS mice. RESULTS: Ica significantly reduced degrees of peritoneal adhesions, decreased quantities and volumes of ectopic lesions and improved reproductive capacity in EMS mice. Moreover, Ica may inhibit ovarian GC senescence and improve ovarian function in EMS mice by regulating NDUFS8/ROS/P53/P21 axis. In vitro experiments demonstrated that Ica may inhibit EMS-FF-induced KGN cell senescence by regulating NDUFS8/ROS/P53/P21 axis. CONCLUSIONS: These findings identify Ica as a GC senescence-inhibiting agent with therapeutic potential in EMS-associated infertility.