Xingling He, Sijing Li, Jiahui Chen, Liyu Lin, Xinyu Li, Xiaojiao Zhang, Yihui Zhang, Xingling Chen, Jinjian Guo, Zhongqi Yang, Lu Lu, Shihao Ni
Atherosclerotic cardiovascular disease (ASCVD) remains the leading global cause of mortality, with substantial residual inflammatory risk persisting despite statin therapy. We identify a c-Rel-driven CD72hi macrophage subset markedly enriched in human and murine atherosclerotic plaques, whose abundance correlates with disease severity. Single-cell transcriptomics and functional assays demonstrate that CD72hi macrophages drive endothelial pyroptosis, oxidative stress and dysfunction via pathological crosstalk through the CXCL12-CXCR4 axis. Through transcriptome-based phenotypic screening, we discover Ilexoside K (IK), a natural triterpenoid saponin, as a dual anti-atherosclerotic and anti-pyroptotic lead compound. Molecular docking, dynamics simulations, and surface plasmon resonance (SPR) validate that IK directly binds CXCR4. In vivo, IK significantly alleviates atherosclerotic plaque burden, dyslipidemia, systemic inflammation and endothelial pyroptosis in high-fat diet-fed ApoE-/- mice with favorable safety. Gain-of-function assays confirm that endothelial CXCR4 overexpression abrogates IK's vasculoprotective effects. This study defines CD72hi macrophages as a key pro-atherogenic subset and establishes IK as a promising CXCR4-associated agent for ASCVD treatment.