Network toxicology and molecular simulation identify key genes and pathways in PFAS-induced premature ovarian...

Premature ovarian insufficiency (POI) is a reproductive disorder characterized by the early loss of ovarian function in women under 40 years of age. PFAS, especially PFOA and PFOS, have been implicated in ovarian dysfunction, but their mechanisms of action remain unclear. In this study, an integrative network toxicology approach was applied, combining target prediction, gene enrichment analysis, machine learning based feature selection, molecular docking, and molecular dynamics simulations, with transcriptomic validation using the GSE127453 dataset. 83 overlapping targets between PFAS and POI were identified. GO enrichment analysis indicated significant involvement in nuclear receptor mediated transcriptional regulation, including steroid hormone receptor and estrogen receptor signalin, KEGG analysis highlighted pathways related to progesterone-mediated oocyte maturation, cellular senescence, and the FoxO signaling pathway, implying dual toxicological mechanisms involving impaired oocyte development and accelerated ovarian cell aging. Eight core genes were identified, including SHBG, CDC25A, TPO, BMP2, MAPK1, CASP3, CDK2, and ESR1. Among them, BMP2, CDK2, SHBG, and TPO were downregulated, while CASP3 and ESR1 were upregulated in POI samples. Molecular docking and dynamics simulations revealed stable, high affinity interactions between PFAS and CASP3, supporting a potential role in apoptosis activation. Nonetheless, further in vitro, in vivo, and mixture-based studies are warranted to substantiate these computational predictions and clarify dose-response relationships.