α‐Ketoglutarate Improves Ovarian Reserve Function in Primary Ovarian Insufficiency by Inhibiting NLRP3‐Mediated Pyroptosis of Granulosa Cells

Scope Premature ovarian insufficiency (POI) is a common female infertility problem, with its pathogenesis remains unknown. The NOD‐like receptor family pyrin domain‐containing 3 (NLRP3)‐mediated pyroptosis has been proposed as a possible mechanism in POI. This study investigates the therapeutic effect of α‐ketoglutarate (AKG) on ovarian reserve function in POI rats and further explores the potential molecular mechanisms. Methods and results POI rats are caused by administration of cyclophosphamide (CTX) to determine whether AKG has a protective effect. AKG treatment increases the ovarian index, maintains both serum hormone levels and follicle number, and improves the ovarian reserve function in POI rats, as evidence by increased the level of lactate and the expression of rate‐limiting enzymes of glycolysis in the ovaries, additionally reduced the expression of NLRP3, Gasdermin D (GSDMD), Caspase‐1, Interleukin‐18 (IL‐18), and Interleukin‐1 beta (IL‐1β). In vitro, KGN cells are treated with LPS and nigericin to mimic pyroptosis, then treated with AKG and MCC950. AKG inhibits inflammatory and pyroptosis factors such as NLRP3, restores the glycolysis process in vitro, meanwhile inhibition of NLRP3 has the same effect. Conclusion AKG ameliorates CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis, which provides a new therapeutic strategy and drug target for clinical POI patients. AKG protects against CTX‐induced POI by inhibiting NLRP3‐mediated pyroptosis of granulosa cells, restoring the glycolysis and improving ovarian reserve function.(Created with BioRender.com).