Ninjurin1 in cardiovascular and vascular biology: From molecular mechanisms to therapeutic opportunities

Abstract Background Ninjurin1 (NINJ1) is a transmembrane protein originally identified as a nerve injury‐induced adhesion molecule. Recent discoveries have revealed its essential role in plasma membrane rupture (PMR) during lytic cell death, positioning NINJ1 as a critical mediator at the intersection of vascular biology, inflammation, and programmed cell death. Its complex and context‐dependent biology makes it a compelling target for cardiovascular research. Methods This review comprehensively synthesizes evidence from structural, molecular, cellular, and in vivo studies on NINJ1. We integrated data on NINJ1's structural biology, its cell‐type‐specific roles in endothelial cells, macrophages, smooth muscle cells, and pericytes, and its contributions to major cardiovascular diseases, including atherosclerosis, myocardial infarction, aortic aneurysm, and ischemia‐reperfusion injury. Emerging therapeutic strategies targeting NINJ1 oligomerization were also evaluated. Results NINJ1 exhibits a fundamental biological paradox in cardiovascular pathophysiology. In its membrane‐bound form, NINJ1 transitions from an autoinhibited homodimer to an active polymeric filament upon cell death stimulation, executing PMR and releasing damage‐associated molecular patterns (DAMPs) that amplify vascular inflammation. In contrast, its soluble MMP‐9‐cleaved ectodomain (sNINJ1) suppresses macrophage activation, attenuates monocyte‐endothelial interactions, and exerts potent atheroprotective effects. NINJ1 is dynamically regulated across multiple cardiovascular pathologies and contributes to endothelial dysfunction, plaque instability, myocardial injury, and pericyte‐mediated vascular remodeling. Conclusions NINJ1 is a pivotal and therapeutically tractable mediator of cardiovascular inflammation. Its dual roles in promoting PMR‐driven DAMP release and in limiting inflammation through sNINJ1 signaling provide complementary avenues for therapeutic intervention. Strategies targeting NINJ1 oligomerization or exploiting sNINJ1‐mimetic peptides hold promise for the treatment of inflammatory cardiovascular diseases and warrant further translational investigation. Key points Membrane‐bound NINJ1 oligomerizes into amphipathic filaments to execute plasma membrane rupture (PMR) during lytic cell death, releasing DAMPs that propagate vascular inflammation across multiple cardiovascular pathologies. The soluble MMP‐9‐cleaved ectodomain of NINJ1 (sNINJ1) exerts anti‐inflammatory and atheroprotective effects, creating a functional paradox in which a single protein can both promote and restrain cardiovascular inflammation. NINJ1 exerts cell‐type‐specific functions in endothelial cells, macrophages, smooth muscle cells and pericytes, contributing to atherosclerosis, myocardial infarction, aortic aneurysm and ischemia‐reperfusion injury. Targeting NINJ1 oligomerization or utilizing sNINJ1‐mimetic peptides represents a novel therapeutic strategy with potential for treating inflammatory cardiovascular diseases.