ObjectivePer- and polyfluoroalkyl substances (PFAS) are omnipresent, persistent contaminants associated with rising ovarian cancer incidence; however, the molecular circuitry linking PFAS to ovarian tumorigenesis remains obscure.MethodsHere, an integrated network toxicology–molecular docking pipeline was developed to interrogate ten environmentally abundant PFAS.ResultsComprehensive interactome mapping identified 1,042 PFAS–protein interactions that converge on eight transcriptional hubs (HDAC1, SIRT1, ESR1, RXRA, PTGS2, MMP9, HDAC2 and HDAC3), subsequently validated as significantly overexpressed in ovarian tumours versus normal tissue pathway enrichment indicated that these mediators synchronize epigenetic silencing, estrogen signalling, inflammatory prostaglandin synthesis and extracellular-matrix remodelling, thereby may coordinate processes potentially associated with PFAS-associated initiation and progression. Competitive docking further showed that long-chain PFOS and PFOA are predicted the strongest binding affinities to the catalytic domains of HDACs 1–3, mechanistically explaining the observed transcriptomic alterations. Human ovarian granulosa-like tumor cell line (KGN) was exposed to PFOA, which works as a representative PFAS compound, showed a significant increase of cell proliferation and migration, leading to an alteration of gene expression previously identified by network toxicology.DiscussionOur findings provides a systems-level predictive framework for understanding PFAS-associated ovarian oncogenesis, furnish quantitative biomarkers for exposure–response modelling, and prioritize HDAC inhibition as prioritized candidate mediators to mitigate PFAS-related cancer risk with immediate translational implications for public-health protection and regulatory guideline revision.