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Background: Per- and polyfluoroalkyl substances (PFAS) are human-made chemicals that accumulate in the human body and the environment over time. Humans are primarily exposed to PFAS through drinking water, food, consumer products, and dust. These exposures can have many adverse health effects, including cardiovascular diseases (CVDs) and factors contributing to CVDs. This study identified the molecular mechanisms of CVDs caused by PFAS. Methods: For this purpose, various computational tools, such as the Comparative Toxicogenomic Database, ShinyGO, ChEA3, MIENTURNET, GeneMANIA, STRING, and Cytoscape, were used to conduct in silico analyses. Results: The results showed that 10 genes were common between PFAS and CVDs, and among these common genes, the PPAR signaling pathway, fatty acid metabolic processes, and lipid binding were the most significantly associated gene ontology terms. Among the top 10 transcription factors (TFs) related to these common genes, peroxisome proliferator-activated receptor gamma and androgen receptor were the most prominent. Additionally, hsa-miR-130b-3p, hsa-miR-130a-3p, and hsa-miR-129-5p were featured microRNAs involved in PFAS-induced CVDs. Finally, PPARAand PPARGwere identified as core genes involved in PFAS-induced CVDs. Conclusion: These findings may contribute to a better understanding of the molecular mechanisms and reveal new potential targets in PFAS-induced CVDs.Graphical Abstract

•Excitotoxicity may be involved in the pathology of many neurological conditions, such as Alzheimer's and Huntington's disease.•Recently, it was revealed that physical interaction of extra-synaptic NMDARs with TRPM4 is a requirement for excitotoxicity.•The discovery of non-toxic compounds that only block extra-synaptic NMDAR/TRPM4 interactions is of great importance.•C8-15 could block the extra-synaptic NMDAR/TRPM4 interaction without impairing physiological functions of synaptic NMDARs.