Elucidating the impact of PFAS exposure on diabetes through integrated network toxicology.

Per- and polyfluoroalkyl substances (PFAS) are environmental pollutants linked to various health concerns, including metabolic disorders like diabetes. This study investigates the molecular mechanisms by which PFAS exposure influences diabetes through network toxicology and functional genomics approaches. We utilized the GSE25724 diabetes-related dataset to identify differentially expressed genes (DEGs) associated with PFAS exposure using the Comparative Toxicogenomics Database (CTD). Our methodologies included enrichment analyses, single-sample Gene Set Enrichment Analysis (ssGSEA), Protein-Protein Interaction (PPI) network construction, immune cell infiltration analysis, molecular docking, and validation experiments on HepG2 cells. Our analysis identified 34 DEGs linked to both diabetes and PFAS exposure. Enrichment analysis indicated these genes' involvement in critical pathways such as adipocytokine signaling, insulin secretion, and glucose homeostasis. ssGSEA revealed that inflammation-related pathways were significantly upregulated, while metabolic and stress response pathways were downregulated in the T2DM group. The PPI network pinpointed ATP2A2, INS, and NFE2L2 as key hub genes, which were validated to be significantly downregulated under PFAS exposure in HepG2 cells. The diagnostic potential of these genes was strong, with AUC values over 0.88. Immune cell infiltration analysis showed significantly altered immune profiles in the T2DM group. Molecular docking demonstrated stable binding between PFAS compounds and key genes, providing insights into potential molecular interactions. Our findings suggest that PFAS exposure disrupts crucial gene functions and biological pathways associated with diabetes, highlighting the significant impact of environmental toxicants on metabolic health. This underlines the need for further research into PFAS's role in diabetes pathophysiology.