Environmental Exposure to Triclosan Promotes Rheumatoid Arthritis via KEAP1/NRF2 Inhibition and Subsequent IL-17 Signaling Activation

Abstract Triclosan (TCS) is a ubiquitous environmental contaminant known for its endocrine-disrupting and immunotoxic effects, yet its role in autoimmune diseases, including rheumatoid arthritis (RA), remains poorly understood. Here, we observed that serum TCS levels were significantly elevated in RA patients compared to healthy controls. In vivo, TCS dose-dependently aggravated collagen-induced arthritis in mice, with KEAP1 upregulation, synovial hyperplasia, and elevated serum TNF-α, IL-6, and IL-1β. In rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), TCS promoted a pro-inflammatory and aggressive phenotype with enhanced cytokine production, proliferation, migration, and invasion. Mechanistically, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) confirmed direct TCS-KEAP1 binding (KD = 4.5 μM), supported by molecular docking (binding energy: −7.93 kcal/mol) and molecular dynamics (MD) simulations. This interaction led to KEAP1 upregulation, enhanced KEAP1-NRF2 binding, and NRF2 sequestration in the cytoplasm via a degradation-independent mechanism, impairing its nuclear translocation and transcriptional activity. Consequently, NRF2 blockade led to sustained oxidative stress and IL-17/MAPK/NF-κB cascade activation, which NAC rescue experiments validated as oxidative stress-driven. Critically, restoring NRF2 nuclear entry via KEAP1 silencing or NRF2 activation effectively reversed these pro-arthritic effects. These findings identify TCS as an environmental risk factor for RA that subverts the KEAP1/NRF2 redox checkpoint to perpetuate IL-17-mediated joint destruction.