Icariin attenuates premature ovarian insufficiency via a phytoestrogenic mechanism mediated by the ERβ/SIRT3 pathway.

Abstract

Premature ovarian insufficiency (POI) affects up to 1&#xa0;% of the female population worldwide. Icariin (ICA) has shown promising potential for the alleviation of POI. However, the molecular mechanisms underlying the protective effects of ICA warrant further exploration. In this study, we aimed to elucidate the mechanisms by which ICA improves ovarian function via antioxidant effects mediated by the ER&#x3b2;/SIRT3 pathway. Cisplatin-induced murine models of POI were used to systematically investigate the cytoprotective efficacy of ICA by comprehensive ovarian histopathological analysis, follicular quantification, estrous cycle monitoring, serum hormonal profiling, and the evaluation of biomarkers of ovarian oxidative stress and apoptosis. Then, an integrated methodological approach encompassing molecular docking, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, was implemented to analyze the mechanism of the ER&#x3b2;/SIRT3 pathway in conferring antioxidant protection in vitro against ICA. In cisplatin-induced murine models of POI, the administration of ICA significantly elevated follicle counts, restored normal estrous cyclicity, and normalized serum hormone levels (p&#xa0;<&#xa0;0.01). Furthermore, ICA activated the ER&#x3b2;/SIRT3 pathway, thus ameliorating cisplatin-induced ovarian oxidative damage. In vitro, ICA conferred protection against HO-induced injury in KGN cells. Mechanistically, ICA enhanced the binding of ER&#x3b2; to the promoter of the SIRT3 gene, thereby promoting the activation of SIRT3. Critically, the protective effects of ICA were abolished following the pharmacological inhibition of ER&#x3b2; or SIRT3. ICA ameliorated cisplatin-induced ovarian oxidative damage by activating the ER&#x3b2;/SIRT3 pathway, providing scientific evidence for its potential as a therapeutic agent for POI. This finding facilitates further optimization of drug design and could enhance the quality-of-life for patients with POI.