Per- and polyfluoroalkyl substances trigger autoimmune diseases through inflammatory cytokines-IL-17/Th17 signaling axis

This study systematically investigates the mechanisms by which per- and polyfluoroalkyl substances (PFAS) promote immune dysregulation and trigger autoimmune diseases (ADs). Using an integrated network toxicology and bioinformatics approach, we identified core molecular interactions between PFAS and five ADs—rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), and vasculitis. By combining data from STITCH, SwissTargetPrediction, Comparative Toxicogenomics Database, GeneCards, and OMIM, we identified shared targets linked to both PFAS exposure and AD pathogenesis. Functional enrichment analysis was performed using DAVID, and protein-protein interaction networks were constructed with STRING and visualized in Cytoscape to highlight core targets. Gene expression data from the GEO database revealed the upregulation or downregulation of these targets across these ADs. Molecular docking performed with CB-Dock2 confirmed robust binding between six PFAS and core targets, notably IL1B, TNF, IL6 and ALB. Importantly, we identified a common pathological mechanism involving PFAS-mediated disruption of the inflammatory cytokine axis (IL1B, TNF, IL6) and IL-17/Th17 signaling pathway, which triggers ADs. Furthermore, compared to PFOS, its alternative 6:2 Cl-PFESA showed higher binding affinity to core targets, suggesting greater environmental and health risks that warrant re-evaluation. In conclusion, our research has provided novel and important insights into environmental health and ADs by clarifying core targets and potential mechanisms, and has expanded the evidence into the molecular mechanism of PFAS-induced immunotoxicity and linking PFAS exposure to ADs. • PFAS exposure may serve as an environmental trigger in development of autoimmunity. • Core targets (ALB, IL6, TNF, IL1B) and IL-17 signaling are shared mechanism of ADs. • PFAS triggers cytokine dysregulation and Th17/Treg imbalance in autoimmunity. • Established a robust framework to elucidate environmental immunotoxicity of PFAS. • The new substitute 6:2 Cl-PFESA may have higher toxicological risk than PFOS.