BACKGROUND: In-stent restenosis (ISR) is one of the most significant complications following percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD). Ferroptosis is a novel cell death mode characterized by iron overload and lipid peroxidation. However, the role of ferroptosis in vascular smooth muscle cells (VSMCs) regulating neointimal formation during restenosis remains unclear. OBJECTIVE: The current study aims to reveal the molecular targets for neointimal hyperplasia through integrated analysis of data from gene expression omnibus (GEO) databases and single-cell sequencing (scRNA-Seq). METHODS AND RESULTS: In this study, we screened ten common differentially expressed genes (Co-DEGs) including BID, SP1, NCF2, HERPUD1, RICTOR, LAMP2, CAT, ACSL1, CS, and ANO6 from the GEO and FerrDb V2. GO/KEGG analyses indicated that metabolic reactions, particularly glyoxylate and dicarboxylate metabolism pathways, are the main molecular events. Immune infiltration analysis showed significant correlations between the expression of Co-DEGs and the infiltration of macrophages, dendritic cells, eosinophils, and neutrophils. Moreover, we identified SP1 as a potential therapeutic target associated with ferroptosis in ISR and constructed a lncRNA-miRNA-SP1 regulatory network. Using scRNA-Seq data to validate the expression of Co-DEGs in the neointima, we found that metabolic pathways such as carbon metabolism, peroxisomes, and reactive oxygen species were enriched. Immune infiltration examined the relationship between Co-DEGs and immune cells, revealing negative correlation between SP1 and neutrophils, and positive correlation between BID and macrophages. CONCLUSION: The integrated analyses identified SP1 as a key regulator of ferroptosis in ISR and proposed its potential to be a novel therapeutic target of ISR. The construction of ceRNA network based on SP1 might contribute to new treatment strategy and drug development for ISR.