The CD47 signaling axis regulates the formation and vulnerability of atherosclerotic plaques: mechanism analysis and targeting strategies.

CD47-centered signaling, involving the functionally distinct CD47-SIRPα and TSP-1-CD47 axes, has been increasingly implicated in the regulation of vascular inflammation, cellular clearance, and atherosclerotic plaque remodeling. This review examines these signaling pathways within two interrelated pathological dimensions: plaque formation and plaque vulnerability. During plaque formation, TSP-1-CD47 signaling may contribute to endothelial dysfunction, leukocyte recruitment, vascular smooth muscle cell phenotypic modulation, and macrophage foam cell formation. In particular, atherosclerosis-specific experimental evidence supports a TSP-1-CD47-Nox1-dependent mechanism that promotes receptor-independent native low-density lipoprotein uptake through macrophage macropinocytosis. During plaque progression, the CD47-SIRPα axis functions primarily as an inhibitory phagocytic checkpoint. Engagement of macrophage SIRPα recruits SHP-1/2-dependent inhibitory signaling, suppresses cytoskeletal rearrangement, and impairs efferocytosis of apoptotic cells and lipid-rich cellular remnants, thereby contributing to secondary necrosis, necrotic core expansion, and persistent inflammation. In contrast, proposed effects of CD47-centered signaling on macrophage polarization, autophagy, and angiogenic responses are more context-dependent and are supported largely by indirect evidence derived from oncology, ischemic injury, wound-healing, metabolic disease, or in vitro models. To clarify these mechanistic boundaries, we classify the available evidence according to its source and directness, distinguishing atherosclerosis-specific findings from related vascular evidence and hypothesis-generating observations. Finally, we review current CD47-targeted therapeutic strategies and their translational limitations, including anemia, thrombocytopenia, off-target phagocytosis, uncertain effects on vascular repair, and the lack of cardiovascular clinical evidence. Although plaque-targeted delivery and cell-selective modulation may improve therapeutic specificity, the efficacy and long-term safety of CD47-targeted interventions in human atherosclerotic cardiovascular disease remain unproven. Finally, we address key translational bottlenecks-including systemic hematological toxicities like anemia-and discuss how plaque-specific biomimetic nano-delivery systems represent the mandatory path forward to safely realize the therapeutic potential of CD47-targeted interventions in clinical cardiology.