Molecular mechanism by which perfluorooctane sulfonate regulates the initiation and progression of prostate cancer via the ENTPD5-adenine axis.

Perfluorooctane sulfonate (PFOS), a persistent member of the per- and polyfluoroalkyl substances family, has been increasingly associated with adverse carcinogenic effects; however, the molecular basis by which PFOS may contribute to prostate cancer (PCa) initiation and progression remains poorly defined. In this study, we aimed to systematically elucidate the mechanisms underlying PFOS-associated prostate carcinogenesis, with particular emphasis on the identification of actionable molecular targets and metabolically relevant pathways. By integrating network toxicology, transcriptomic differential analysis, weighted gene co-expression network analysis, multi-algorithm machine learning, single-cell and spatial transcriptomics, metabolomics, and structural modeling, we identified a four-gene core signature consisting of APOF, B3GAT1, CGREF1, and ENTPD5. Among these candidates, ENTPD5 emerged as the most prominent PFOS-associated target, showing marked enrichment in epithelial compartments across both single-cell and spatial datasets. Further integrative analyses converged on purine metabolism as a shared pathogenic vulnerability, and increased ENTPD5 expression was accompanied by elevated adenine abundance, supporting the existence of an ENTPD5-centered metabolic axis. Molecular docking and molecular dynamics simulations further suggested stable binding of PFOS to ENTPD5. In addition, immunohistochemical evidence consistently confirmed ENTPD5 upregulation in prostate cancer tissues. Collectively, our findings support a PFOS-ENTPD5-adenine mechanistic axis that may promote prostate cancer initiation and progression through purine metabolic reprogramming, and provide a potential foundation for the development of exposure-related biomarkers and preventive intervention targets in PCa.