Potential molecular links between triclosan exposure and osteoarthritis: An integrative systems toxicology study.

Osteoarthritis (OA) is a chronic disease affecting the entire joint, influenced by a combination of inflammatory, metabolic, immune, and environmental factors. Triclosan (TCS), a commonly used antimicrobial compound, has been linked to oxidative and immune disturbances; however, its molecular relevance to OA remains to be elucidated. This study integrated network toxicology, bulk transcriptomics, cross-cohort machine learning prioritization, immune infiltration analysis, single-cell transcriptomic analysis, molecular docking, molecular dynamics simulations, and primary chondrocyte experiments. Thirty candidate genes related to both TCS and OA were identified, with CBR3, MAOA, MMP13, and AVPR1A being prioritized. Among these, CBR3 exhibited the most stable contribution to model predictions, widespread expression across OA chondrocyte subpopulations, and significant associations with inferred immune-cell composition. Supporting molecular docking and dynamics analyses indicated structural compatibility and dynamic feasibility between TCS and the four candidate proteins. In primary rat chondrocytes, low-dose TCS heightened reactive oxygen species (ROS) accumulation, upregulated Cbr3 and Mmp13, downregulated Col2a1, Maoa, and Avpr1a, and increased CBR3 protein levels, with specific redox-related and matrix-related alterations becoming more pronounced under IL-1β stimulation. These findings contribute to a model that links TCS-associated redox disturbances to OA-relevant chondrocyte stress and matrix remodeling, providing candidate molecular connections for future mechanistic validation.