Perfluoroalkyl Substance (PFAS) Mixtures Drive Rheumatoid Arthritis Risk Through Immunosuppression: Integrating Epidemiology and Mechanistic Evidence.

Perfluoroalkyl substances (PFASs) possess immunosuppressive properties. However, their association with rheumatoid arthritis (RA) risk remains inconclusive across epidemiological studies. This study integrates population-based and mechanistic evidence to clarify the relationship between PFAS exposure and RA. We analyzed 8743 U.S. adults from the NHANES (2005-2018), assessing individual and mixed exposures to PFOA, PFOS, PFNA, and PFHxS using multivariable logistic regression, Bayesian kernel machine regression, quantile g-computation, and weighted quantile sum models. Network toxicology and molecular docking were utilized to identify core targets mediating immune disruption. The results showed that elevated PFOA (OR = 1.63, 95% CI: 1.41-1.89), PFOS (OR = 1.41, 1.25-1.58), and PFNA (OR = 1.40, 1.20-1.63) levels significantly increased RA risk. Mixture analyses indicated a positive joint effect (WQS OR = 1.06, 1.02-1.10; qgcomp OR = 1.26, 1.16-1.38), with PFOA as the primary contributor. Stratified analyses revealed stronger effects in females (PFOA Q4 OR = 3.75, 2.36-5.97) and older adults (≥60 years). Core targets included EGFR, SRC, TP53, and CTNNB1. PFAS mixtures increase RA risk, dominated by PFOA and modulated by sex/age. These findings help reconcile prior contradictions by identifying key molecular targets and vulnerable subpopulations, supporting regulatory attention to PFAS mixture exposure.