Systems-Level Bioinformatic Characterization of Obesity-Associated Molecular Mechanisms Linked to Per- and Polyfluoroalkyl Substances (PFAS)

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants implicated in obesity, but shared molecular mechanisms across individual PFAS remain unclear. We applied an integrative network-toxicology framework to identify obesity-related targets shared by four European Food Safety Authority (EFSA)-priority PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS). Chemical–gene interactions and phenotypes were retrieved from the Comparative Toxicogenomics Database (CTD) and analyzed using Cytoscape/STRING/CytoHubba, ToppGene, Metascape, and Gene Expression Omnibus (GEO) transcriptomic datasets. Of 122, 131, 100, and 49 obesity-associated genes identified for PFOA, PFOS, PFNA, and PFHxS, respectively, 28 were shared. Network analysis prioritized PPARA, PPARG, TNF, ADIPOQ, APOE, IL6, LPL, PPARD, PLIN1, and FASN, while enrichment highlighted nuclear-receptor activity, lipid and nutrient responses, adipogenesis, and peroxisome proliferator-activated receptor (PPAR) signaling. These patterns persisted using a CTD obesity-specific reference background and in a six-gene subset with directional mRNA evidence. Metascape identified an IL6–TNF–ADIPOQ–SERPINE1 module, while 39 phenotypes were shared with obesity. Independent GEO validation supported 18 of 28 genes (64.3%), with PEX11A responsive to all four PFAS. Overall, the findings define a hypothesis-generating signature of molecular convergence and prioritize metabolic, inflammatory, endocrine, and redox-sensitive processes for experimental validation.