Quercetin Boosts Pulsatile Gonadotropin‐Releasing Hormone Release to Improve Luteal Function via Inhibiting NF‐κB/NLRP3‐Mediated Neuron Pyroptosis

Abstract Scope : Luteal phase deficiency (LPD) is the main cause of infertility without an effective cure. Quercetin (QUE) is a bioactive flavonoid with antioxidant properties, while its role in treating LPD remains unclear. This study aims to investigate the therapeutic effects of QUE on infertility and menstrual disorders induced by LPD, thus further exploring the underlying mechanism. Methods and results : Mifepristone‐induced rats are used to explore the protective effects of QUE against LPD. QUE stimulates the spontaneous secretion of progesterone to improve luteal function and endometrial receptivity in LPD rats by activating the kisspeptin/GPR54 system to facilitate the gonadotropin‐releasing hormone (GnRH) pulsatility. Bioinformatics analysis reveals that the core mechanism of QUE in treating LPD is to attenuate the GnRH neuron pyroptosis by inhibiting the NF‐κB pathway, which is further verified in LPD rats and lipopolysaccharide (LPS)‐treated GT1‐7, as QUE significantly reduces the expression of key factors concerning NF‐κB pathway and NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome. Conclusion : This study first proposes that neuron pyroptosis‐induced GnRH pulsatility disruption accounts for the pathogenesis of LPD, and QUE facilitates the pulse secretion of GnRH to boost the spontaneous progesterone secretion by inhibiting NF‐κB/NLRP3‐mediated neuron pyroptosis, which provides a new therapeutic target and strategy for LPD.