Exploring immune-inflammatory cross-talk in atherosclerosis using AI-enhanced multi-omics approaches.

Atherosclerosis is a complex chronic inflammatory disease characterized by lipid accumulation, vascular smooth muscle cell (VSMCs) proliferation, and immune cell infiltration. However, the heterogeneity and functional dynamics of VSMCs in atherosclerotic lesions have not been systematically elucidated. In this study, we integrated single-cell transcriptomics with spatial transcriptomics analysis to delineate the developmental trajectories and functional states of VSMC subsets. Our analysis identified a distinct LUM + VSMCs subpopulation residing at an early stage of differentiation, marked by elevated cellular plasticity, stemness features, and strong activation of pro-inflammatory signaling pathways. Spatial transcriptomics and in vitro functional assays—including EdU incorporation, apoptosis quantification, and cell viability assays—further validated LUM as a key regulator promoting VSMC proliferation and inflammation. Importantly, the C0 LUM + VSMCs were predicted to interact extensively with endothelial cells and macrophages through CD99, MIF, and CCL-mediated signaling axes, underscoring their role as dedifferentiated, pro-inflammatory effector cells contributing to disease progression. These findings highlight the power of big data-enabled single-cell approaches in identifying cell-type–specific mechanisms and offer new avenues for precision diagnostics and biomarker discovery in inflammatory vascular diseases.