Background <p>Intraplaque hemorrhage (IPH) is a key driver of carotid plaque rupture and ischemic events. However, the molecular mechanisms linking immune infiltration to pathological neovascularization in the IPH microenvironment remain poorly defined. This study aimed to elucidate the critical role of the ADAM8-SPP1-ITGB1 signaling axis in driving this ischemic phenotype.</p> Methods <p>Transcriptomic analyses were performed on bulk (<i>n</i> = 230) and single-cell (<i>n</i> = 15) RNA-seq datasets and included weighted gene coexpression network analysis (WGCNA), survival analysis, cell clustering, virtual knockout, and cell–cell communication. In vivo, ApoE knockout mice fed a high-fat diet were evaluated using ultrasound, H&amp;E staining, immunofluorescence, and ELISA. In vitro, following siRNA-mediated ADAM8 knockdown, the lipid accumulation, oxidative stress, and apoptosis of ox-LDL-stimulated RAW264.7 macrophages were assessed. HUVECs were subjected to lentivirus-mediated ITGB1 knockdown and treated with recombinant SPP1 to assess cellular proliferation, migration, and angiogenesis.</p> Results <p>ADAM8 was identified as a robust diagnostic (AUC = 0.935) and prognostic (HR = 2.659) biomarker for the ischemic phenotype of IPH. Single-cell clustering and metabolic analysis revealed a distinct ADAM8⁺SPP1⁺ macrophage subset characterized by active glycolysis and a hypoxic state. Virtual knockout analyses, corroborated by in vitro knockdown experiments, confirmed that ADAM8 drives SPP1 expression. Cell-cell communication analysis indicated that this macrophage subpopulation is linked to angiogenic endothelial cells via the SPP1-ITGB1 axis. In vivo, carotid atherosclerotic mice exhibited enrichment of ADAM8⁺SPP1⁺ macrophages and elevated serum SPP1 levels. In vitro, ADAM8 downregulation in RAW264.7 macrophages alleviated lipid accumulation, ROS generation, apoptosis, and inflammation. Furthermore, recombinant SPP1 significantly promoted HUVEC proliferation, migration, and angiogenesis. Importantly, these proangiogenic effects were completely abolished by lentivirus-mediated ITGB1 knockdown.</p> Conclusions <p>ADAM8⁺SPP1⁺ macrophages promote IPH and plaque instability via the SPP1-ITGB1 angiogenic axis and are potential therapeutic targets for high-risk atherosclerosis.</p> Graphical Abstract <p></p>