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BACKGROUND Erectile dysfunction and atherosclerosis are common cardiovascular complications in diseases. Clinical associations between erectile dysfunction and atherosclerosis have been noticed, but the specific mechanisms are not illustrated adequately. OBJECTIVES The aim of the study was to further mine associated pathological mechanisms and genetic alterations of atherosclerosis in diabetes mellitus-related erectile dysfunction (DMED). MATERIALS AND METHODS Significant atherosclerosis-related genes (ASRGs) were identified from transcriptome data of DMED and ASRG sets from DisGeNET and GeneCard databases. Functional enrichment and immune infiltration analyses were performed to clarify the biological roles and pathways as well as immune responses of significant ASRGs. A protein-protein interaction (PPI) network was constructed and gene clusters were performed. Then, data of diabetic plaques and high-glucose cavernosum endothelial cells was analyzed for validation. And hub ASRGs were identified. Finally expressed pattern of hub ASRGs were explored by single-cell profiling and immune analysis. RESULTS In total, 202 significant ASRGs including 100 up-regulated and 102 down-regulated genes were identified. These genes were related to endothelial cell migration, inflammatory response, regulation of oxidative stress and immune response. In immune infiltration, immature dendritic cell and monocyte showed differential expression between the DMED and control groups, A PPI network containing 135 nodes was constructed. A hub-ASRG signature consisting of HBEGF, LOX, NQO1 and VLDLR was obtained by multi-omics validation. In addition, Functional enrichment analysis revealed that hub ASRGs were involved in oxidoreductase activity and extracellular matrix organization. DISCUSSION AND CONCLUSION We explored atherosclerosis-related genetic changes and signaling pathways in DMED. HBEGF, LOX, NQO1 and VLDLR were identified as hub ASRGs. These may serve as potential biomarkers for the clinical management of atherosclerosis and preventing further cardiovascular risks in DMED. This article is protected by copyright. All rights reserved.