Unraveling the toxicological mechanisms of PFAS in metabolic diseases by network toxicology and molecular docking.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS), man-made fluorinated chemicals, are widely distributed in the environment and can enter human habitats through various pathways. However, the mechanisms by which PFAS affect metabolic health are not fully understood. OBJECTIVES: Our goal is to systematically uncover the key molecular pathways through which PFAS influence metabolic diseases. METHODS: We selected five representative metabolic diseases: type 2 diabetes mellitus (T2DM), osteoporosis, hyperuricemia, obesity, and non-alcoholic fatty liver disease (NAFLD). Network toxicology methods were used to integrate data from the Comparative Toxicogenomics Database (CTD) and GeneCards, identifying important PFAS-related targets for each disease. We created protein-protein interaction (PPI) networks using the STRING platform and subsequently performed topological analysis in Cytoscape, which revealed 20 core targets associated with PFAS and metabolic diseases. These include INS, PPARG, TP53, IL6, ALB, PTGS2, APOE, CAV1, SIRT1, CD44, LPL, GCK, TLR4, NFKB1, NOS3, EP300, G6PC, SREBF1, PLIN1, and RXRA. Molecular docking and molecular dynamics simulations were used to assess PFAS interactions with these target proteins. RESULTS: Results showed that PFAS molecules bind strongly to multiple core targets. Ranking targets by average binding energy highlighted those with the greatest PFAS binding potential. GO and KEGG enrichment analyses indicated these targets are involved in critical processes like glucose metabolism, lipid metabolism, purine metabolism, calcium-phosphorus metabolism, and NAFLD. CONCLUSIONS: Our study offers novel insights into the close link between environmental PFAS exposure and metabolic diseases, providing a strong foundation for developing personalized prevention and targeted treatments for these conditions.