INTRODUCTION: Cardiovascular disease (CVD) caused by atherosclerosis (AS) remains the leading cause of mortality in developed countries. Understanding cellular heterogeneity within the inflammatory microenvironment is crucial for advancing disease management strategies. This study investigates the regulatory functions of distinct cell populations in AS pathogenesis, focusing on the interaction between vascular smooth muscle cell (VSMC)-derived ITLN1 METHODS: We employed single-cell RNA sequencing to characterize cell populations within AS plaques. Correlation analyses and the CellChat package were utilized to elucidate intercellular communication networks among various cell types. The functional roles of key subsets of macrophages and VSMCs were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Pseudotime trajectory analysis was conducted to explore the dynamics of VSMC differentiation. Additionally, spatial transcriptomics analysis was used to demonstrate the physical interactions between different cell subpopulations. RESULTS: We identified significant infiltration of macrophage clusters in AS, with SPP1 DISCUSSION: Our findings underscore the critical crosstalk between ITLN1