Yikun formula ameliorates cyclophosphamide-induced premature ovarian insufficiency associated with suppression of AGE/RAGE-related NF-κB and p38 MAPK signaling

Background Premature ovarian insufficiency (POI) is an important cause of impaired female fertility. Yikun Formula (YKF), a traditional Chinese medicine prescription, has shown clinical utility in the treatment of POI, but the molecular basis underlying its protective effects remains unclear. Methods A POI rat model was generated by cyclophosphamide (CTX) administration, followed by intervention with different doses of YKF. Estrous cycle changes, serum hormone profiles, ovarian morphological alterations, oxidative stress status, granulosa cell apoptosis, and fertility-related outcomes were analyzed. In parallel, AGEs-induced injury was established in KGN cells to investigate the cellular mechanisms of YKF. Cell survival, apoptotic response, reactive oxygen species (ROS) production, and changes in inflammatory mediators and pathway-related proteins associated with AGE-RAGE/NF-κB and p38 MAPK signaling were determined. Results YKF treatment markedly improved ovarian function in CTX-induced POI rats, as reflected by recovery of estrous cycle regularity, correction of hormone disturbances, improvement of follicular development, attenuation of oxidative damage and granulosa cell apoptosis, and enhancement of reproductive capacity. In AGEs-stimulated KGN cells, YKF increased cell survival and reduced apoptosis and ROS generation. These effects were accompanied by suppression of AGE-RAGE signaling, reduced activation of NF-κB and p38 MAPK, and downregulation of the inflammatory cytokines IL-6 and TNF-α. Conclusion YKF exerts protective effects against POI by restraining AGE-RAGE-associated inflammatory signaling and its downstream NF-κB/p38 MAPK cascade, thereby alleviating oxidative stress and granulosa cell apoptosis. The present findings support the potential value of YKF as a therapeutic strategy for POI.