Mechanistic insights into PFAS derivatives-induced coronary heart disease and atherosclerotic renal artery stenosis via integrated network toxicology and molecular modeling.

Abstract

Per- and polyfluoroalkyl substances (PFAS), such as PFHpA, PFOA, PFNA, and PFDA, are persistent environmental pollutants associated with multiple diseases. This study investigates the toxic mechanisms and pathways by which PFAS derivatives contribute to coronary artery disease (CAD) and renal arteriosclerosis. Using multiple databases, we identified toxic and disease-related targets and constructed a protein-protein interaction (PPI) network via the STRING database to analyze their interactions. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify relevant disease pathways. GO and KEGG results indicated significant enrichment in lipid metabolism, arteriosclerosis, cell proliferation, apoptosis, and inflammation. Molecular docking and dynamics simulations were used to evaluate the binding affinity and stability of PFAS derivatives with key targets. Core regulatory targets within the toxicity network-STAT3, MMP9, NFκB1, CASP3, AKT1, and PPARG-were found to mediate cardiotoxicity and nephrotoxicity through multiple pathways. Docking studies confirmed strong binding affinity (<-5 kcal/mol) between PFAS derivatives and these targets. Molecular dynamics simulations suggested that PFDA binds more stably to MMP9 than to other proteins. These findings indicate that PFAS derivatives may exacerbate renal and coronary arteriosclerosis by modulating lipid and arteriosclerosis signaling pathways and affecting key genes including STAT3, MMP9, and NFκB1. This study highlights potential mechanisms underlying PFAS-induced cardiovascular and renal damage.