Exploring the connection between organophosphate flame retardants and Hyperlipidemia: an integrated analysis using NHANES (2011–2018), network toxicology, and mendelian randomization

Abstract Organophosphorus flame retardants (OPFRs) are ubiquitous contaminants associated with metabolic disorders. This study examined the association between human exposure to OPFRs and hyperlipidemia and explored potential underlying biological mechanisms. Using data from 3,228 adults from the NHANES cycles of 2011–2018, we analyzed associations using weighted multiple logistic regression, restricted cubic spline analysis, and weighted quantile sum regression. Results showed a robust positive association between urinary OPFRs metabolite levels and hyperlipidemia (OR = 1.33, 95% CI: 1.15–1.55, P < 0.01). Cumulative exposure to OPFRs mixtures was also significantly associated with hyperlipidemia (OR = 1.27, 95% CI: 1.09–1.47, P = 0.002). Subsequent network toxicology and Mendelian randomization analyses suggested that OPFRs may be associated with hyperlipidemia by potentially regulating key targets (e.g. TP53, STAT3, AKT1) and activating specific pathways, including those involved in cancer and the PI3K-Akt signaling cascade. This study supports an association between OPFRs exposure and hyperlipidemia and suggests a potential multi-target, multi-pathway regulatory mechanism.