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This study employed a network toxicology strategy to elucidate the toxic mechanisms of polyethylene terephthalate microplastics (PET-MPs) on atherosclerosis (AS). AS is a chronic inflammatory vascular disease that may be aggravated by PET-MPs. By integrating network toxicology, molecular docking, and transcriptome analysis, tumor necrosis factor (TNF), chemokine receptor 4 (CXCR4), CX3C chemokine receptor 1 (CX3CR1), and protein tyrosine phosphatase receptor type C (PTPRC) were identified as core interaction genes between PET and AS. Through bio-enrichment analysis, we discovered that the toxicity of PET is primarily associated with the cascade reaction of vascular inflammation and abnormal macrophage activation. Molecular docking experiments confirmed a strong binding affinity between PET and these targets (<-5.0 kcal/mol). In vitro results showed that PET significantly increased the mRNA levels of TNF-α, CXCR4, CX3CR1, and PTPRC, triggering an inflammatory response and causing chemokine receptor dysfunction. In an AS mouse model, increased aortic plaque area and aortic valve collagen deposition were observed, along with elevated expression of core target genes' mRNA, even without direct exposure to PET-MPs, exhibiting effects consistent with those seen in vitro. Collectively, these studies suggest that PET can induce inflammatory responses and disrupt immune system balance by regulating the expression levels of TNF, CXCR4, CX3CR1, and PTPRC, thus promoting the progression of atherosclerotic diseases. This paper provides the first comprehensive investigation into the impact and mechanisms of microplastics on AS, demonstrating how PET contributes to its development and establishing a basis for identifying new therapeutic targets for cardiovascular diseases linked to microplastics.