Objective:To figure out the possible mechanisms of ferroptosis and explore potential ferroptosis-related genes(FRGs)biomarkers and pharmacological compounds for atherosclerosis(AS).Methods:The AS transcriptome dataset GSE100927 was downloaded from the gene expression omnibus(GEO)database. FRGs were downloaded from FerrDb database. To screen the ferroptosis-related hub genes in AS(FRG-hubs)by weighted gene co-expression network analysis, differential gene analysis, LASSO regression and random forest algorithm. Single-sample gene set enrichment(ssGSEA)analysis was used to evaluate the immunological landscape. Furthermore, transcription factors and miRNAs regulatory networks were constructed by the NetworkAnalyst database, and candidate drugs were searched from DSigDB database. The expression of FRG-hubs was verified by AS model mice.Results:zinc finger E-Box binding homeobox 1(ZEB1), mitogen-activated protein kinase kinase kinase 11(MAP3K11), and cyclin dependent kinase inhibitor 2A(CDKN2A)were identified as FRG-hubs, and the nomogram model based on them demonstrated high reliability and effectiveness. In addition, FRG-hubs and immune cell infiltration showed a significant association. AS patients could be classified into 2 ferroptosis-related cluster with different immune cell infiltration. Predictions were made for 13 transcription factors, 8 miRNAs, and 10 drugs targeting FRG-hubs. The results of qRT-PCR and Western blotting show that compared with the control group, the mRNA and protein expression levels of Map3k11 and Cdkn2a are significantly elevated in the AS model mice, while the expression level of the Zeb1 is significantly decreased.Conclusion:ZEB1, MAP3K11 and CDKN2A may be involved in the occurrence and development of AS by regulating immune-related pathways through ferroptosis.