Revealing the toxicological effects and mechanisms of tris(1-chloro-2-propyl) phosphate exposure on osteoarthritis based on network toxicology, machine learning, and molecular docking.

Osteoarthritis (OA) is a degenerative disease affecting all joints in the body, impacting over 500 million people globally and imposing a significant healthcare burden. Tris(1-chloro-2-propyl) phosphate (TCPP), one of the widely used organophosphate flame retardants (OPFRs), exhibits notable environmental and biological toxicity. However, the role and molecular mechanisms of TCPP exposure in OA remain unclear. This study combined network toxicology, machine learning, and molecular docking techniques to identify key targets and pathways associated with TCPP exposure and OA. A nomogram model was constructed based on the identified hub genes, and immune cell infiltration was evaluated using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. By searching multiple public databases, we obtained 106 TCPP-OA intersection genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these targets primarily participate in immune regulation and inflammatory responses, involving pathways such as the mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) signaling pathways. Machine learning algorithms identified 4 hub genes: GRB2, GSK3B, IL18, and THBS1. Based on these hub genes, we constructed a nomogram model. Calibration curves and decision curves demonstrated the model's sound diagnostic value and clinical efficacy. The CIBERSORT algorithm identified 6 immune cell types with significantly altered infiltration levels during OA progression, and the hub genes were closely associated with multiple immune cell populations. Molecular docking analysis suggested interactions between TCPP and the key proteins. These findings provide the first evidence highlighting the mechanisms through which TCPP may influence OA pathogenesis and identify relevant toxicological targets, laying a foundation for developing strategies to mitigate its effects on OA and improve the understanding of TCPP-related health risks. However, additional in vivo and in vitro studies are required to validate these mechanisms.