Perfluorinated compounds (PFCs) are a well-recognized environmental risk factor for atherosclerosis. However, corresponding atherogenic risk in susceptible populations consuming high-fat diets (HFDs) remains unclear. Here, we found that perfluorooctane sulfonic acid (PFOS), a canonical PFCs, elevated the atherogenic risk in mice fed with HFD, which was characterized by an increased number of pro-inflammatory phenotype macrophages. We also found that macrophages exhibited a metabolic reprogramming to glycolysis, which was attributed to increased intracellular Fe