Integrated network toxicology and bioinformatics approaches explore potential mechanisms linking organophosphate...

Organophosphate flame retardants (OPFRs) are emerging environmental pollutants characterized by high toxicity and persistence; however, their molecular links to rheumatoid arthritis (RA) remain poorly understood. This study employed an integrated approach combining network toxicology, machine learning, and molecular docking to elucidate potential associations between OPFR exposure and RA pathogenesis. By integrating data from multiple databases, we identified 39 overlapping targets associated with both OPFRs and RA. Functional enrichment analysis suggested that these genes were primarily involved in immune regulation and inflammatory responses, potentially through the Toll-like receptor (TLR), NOD-like receptor (NLR), IL-17, and p53 signaling pathways. Using machine learning algorithms, five hub genes-SDC1, SRD5A1, SPP1, COL4A3, and MMP13-were identified as critical biomarkers. Validation using independent Gene Expression Omnibus datasets confirmed their significant differential expression in RA tissues and robust discriminatory potential. Furthermore, Immune-cell infiltration analysis revealed significant correlations between these hub genes and immune cell infiltration, suggesting their potential roles in reshaping the immune microenvironment. Molecular docking and molecular dynamics (MD) simulations further demonstrated strong binding affinities and structural stability in interactions between OPFRs and the proteins encoded by these hub genes in silico. In conclusion, this study identified key genes potentially targeted by OPFRs that are also implicated in RA. These findings provide novel theoretical insights into the environmental risk assessment of OPFRs and identify potential targets for future experimental validation and therapeutic intervention in environmentally associated autoimmune disorders.