To investigate the potential mechanisms by which triclosan (TCS), a widely used endocrine-disrupting chemical commonly found in personal care products, contributes to the progression of rheumatoid arthritis (RA), and to systematically evaluate its immunomodulatory effects using a multi-disciplinary approach that integrates computational toxicology, bioinformatics, and structural biology.

An integrative approach combining network toxicology, machine learning algorithms, and molecular docking was employed to systematically investigate the mechanisms underlying TCS-induced RA. Bioinformatic analyses were conducted to identify interconnected signaling pathways and core target genes associated with TCS exposure, utilizing publicly available databases and enrichment analysis tools. Molecular docking simulations were performed to validate the binding stability, affinity, and interaction modes between TCS and the identified core targets. In addition, immune cell correlation analyses were carried out using single-sample gene set enrichment analysis to explore the potential immunomodulatory roles of the core targets within the RA immune microenvironment.

Bioinformatic analyses revealed multiple critical and interconnected pathways involved in cellular signaling, metabolic processes, and inflammatory regulation, highlighting the complex molecular network through which TCS may influence RA pathogenesis. Four core targets-CASP3, EGFR, HSP90AB1, and MAPK8 were identified in relation to TCS exposure, each playing established roles in apoptosis, cell proliferation, and stress responses. Molecular docking confirmed stable and consistent interactions between TCS and these core targets, with favorable binding energies supporting their relevance as key molecular nodes. Furthermore, the four core targets exhibited positive and broad correlations with several immune cell subtypes, including M1 macrophages, activated natural killer (NK) cells, memory CD4⁺ T cells, and T follicular helper cells, suggesting that TCS may exert regulatory effects on immune cell homeostasis, activation, and differentiation.

Triclosan exerts significant immunomodulatory effects that may play a contributory role in the progression of rheumatoid arthritis by modulating key signaling pathways and influencing immune cell composition. These findings underscore the value of multi-disciplinary approaches, such as network toxicology and machine learning, in evaluating environmental triggers of autoimmune diseases. This study provides a scientific foundation for developing targeted preventive strategies against TCS-associated RA and highlights the need for further experimental validation of the identified core targets.