Triglycerides mediate the relationships of per- and poly-fluoroalkyl substance (PFAS) exposure with nonalcoholic fatty liver disease (NAFLD) risk in US participants.

Nonalcoholic fatty liver disease (NAFLD) is recognized as a significant public health problem worldwide. Several clinical studies have investigated the associations between Per- and poly-fluoroalkyl substances (PFAS) compounds with the risk of NAFLD in general adults, but the mediating effect of triglycerides (TG) was remained unexplored. In this study, 6990 individuals from the National Health and Nutrition Examination Survey (NHANES, 2003-2018) database were enrolled. Firstly, the results of generalized linear models (GLM) and restricted cubic splines (RCS) revealed positive associations of PFAS compounds with NAFLD risk score and liver function, and nearly linear E-R curves indicated no safe threshold. Meanwhile, weighted quantile sum (WQS) regression demonstrated the relationships between PFAS mixtures with NAFLD risk score and liver function, as well as perfluorooctanoic acid (PFOA) was identified as the main contributor to the increased NAFLD risk. Then, mediation analysis was conducted to explore whether serum lipids mediate the relationships. It further highlighted significant mediation effects of TG, with the mediated proportion ranging from 10.4 % to 42.9 %. Finally, sensitivity and stratified analyses were performed, confirming the reliability of these findings. Notably, significant associations were observed in individuals with a BMI ≥ 28, highlighting that these relationships were particularly evident in obese participants. In conclusion, our study suggested that PFAS mixtures exposure may influence NAFLD risk score by mediating TG in human metabolism. This result could provide more comprehensive epidemiological evidence and guide clinical applications.