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This study used European\u2010ancestry GWAS data and two\u2010sample Mendelian randomization to assess potential causal associations between PFOA or PFOS exposure and five cardiovascular diseases. For significant MR findings, network toxicology was integrated with transcriptomic data to identify candidate targets and pathways, followed by machine learning\u2010based prioritization. Immune cell infiltration, single\u2010cell transcriptomic analysis, molecular docking, and molecular dynamics simulation were further applied to explore immune mechanisms and pollutant\u2013protein interactions. Genetically predicted PFOS exposure was associated with an increased risk of peripheral artery disease. Enrichment analysis implicated PPAR and PI3K\u2013Akt signaling pathways, while machine learning based on 129 overlapping genes identified HMOX1, KDR, MMP9, and PPARG as key targets. Immune infiltration and single\u2010cell analyses indicated remodeling of the PAD immune microenvironment, with HMOX1 mainly enriched in macrophages. Virtual knockout highlighted APC\u2010related MHC II antigen presentation, and docking and dynamics simulations supported stable PFOS\u2013HMOX1 binding. 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