{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:42:51Z","timestamp":1790390571915,"version":"4.1.0"},"reference-count":120,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ninjurin1 (NINJ1) is a transmembrane protein originally identified as a nerve injury\u2010induced 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\u2010dependent biology makes it a compelling target for cardiovascular research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010type\u2010specific 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\u2010reperfusion injury. Emerging therapeutic strategies targeting NINJ1 oligomerization were also evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NINJ1 exhibits a fundamental biological paradox in cardiovascular pathophysiology. In its membrane\u2010bound form, NINJ1 transitions from an autoinhibited homodimer to an active polymeric filament upon cell death stimulation, executing PMR and releasing damage\u2010associated molecular patterns (DAMPs) that amplify vascular inflammation. In contrast, its soluble MMP\u20109\u2010cleaved ectodomain (sNINJ1) suppresses macrophage activation, attenuates monocyte\u2010endothelial 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\u2010mediated vascular remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NINJ1 is a pivotal and therapeutically tractable mediator of cardiovascular inflammation. Its dual roles in promoting PMR\u2010driven DAMP release and in limiting inflammation through sNINJ1 signaling provide complementary avenues for therapeutic intervention. Strategies targeting NINJ1 oligomerization or exploiting sNINJ1\u2010mimetic peptides hold promise for the treatment of inflammatory cardiovascular diseases and warrant further translational investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Membrane\u2010bound 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.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The soluble MMP\u20109\u2010cleaved ectodomain of NINJ1 (sNINJ1) exerts anti\u2010inflammatory and atheroprotective effects, creating a functional paradox in which a single protein can both promote and restrain cardiovascular inflammation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>NINJ1 exerts cell\u2010type\u2010specific functions in endothelial cells, macrophages, smooth muscle cells and pericytes, contributing to atherosclerosis, myocardial infarction, aortic aneurysm and ischemia\u2010reperfusion injury.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Targeting NINJ1 oligomerization or utilizing sNINJ1\u2010mimetic peptides represents a novel therapeutic strategy with potential for treating inflammatory cardiovascular diseases.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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