Integrating NHANES and network toxicology to assess the impact of organophosphate flame retardants on cardiovascular disease.

Cardiovascular disease (CVD) pathogenesis involves multifactorial determinants, including environmental pollutants. This study integrated National Health and Nutrition Examination Survey (NHANES) data and network toxicology approaches to investigate the association and underlying molecular mechanisms between organophosphate flame retardant (OPFR) metabolites and CVD risk. Weighted multivariable logistic regression and restricted cubic splines (RCS) were employed to analyze OPFR metabolites-CVD associations using NHANES data. Protein-protein interaction network, expression quantitative trait locus (eQTL)-based Mendelian randomization (MR), colocalization, and molecular docking analyses pinpointed core pathogenic targets. Mediation analysis assessed potential regulatory roles of 731 immune cell features in core target-CVD pathways. Adjusted regression models revealed significant positive associations between urinary bis (2-chloroethyl) phosphate (BCEP) and dibutyl phosphate (DBP) with CVD risk. RCS analysis demonstrated a linear dose-response relationship for BCEP. HSPA1A was identified as the core OPFR metabolites-CVD mediator, with elevated expression increasing CVD risk. Molecular docking provided supportive evidence for strong binding affinities between HSPA1A and metabolites of OPFR. Crucially, mediation analysis demonstrated that HLA DR on HLA DR+ CD4+ T cells partially mediated the effect of HSPA1A on CVD. These findings provide original insights into associations between emerging organic pollutants and CVD risk and establish a theoretical foundation for targeted prevention and therapy.