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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 Fe2+ level. Mechanistic investigation revealed that PFOS directly bound to the iron-storage site on the ferritin heavy chain, subsequently weakening the iron-storage function. Notably, PFCs with acidic substituents and short chains had a higher atherogenic risk, as evidenced in the crucial indicators and observed in a population with a high triglyceride level. These findings highlight the potential atherogenic risk posed by PFCs exposure in susceptible populations consuming HFD and provide a potential intervention target.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgaf153","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T01:45:36Z","timestamp":1746755136000},"source":"Crossref","is-referenced-by-count":4,"title":["Perfluorinated compounds exposure and atherogenic risk characteristics in a high-fat diet condition: In vitro\/in vivo models and population panel study"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6759-0717","authenticated-orcid":false,"given":"Ziyuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Occupational Health and Environmental Health, School of Public Health, Qingdao University , Qingdao 266071 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