NINJ1 as a molecular executor of plasma membrane rupture: from lytic cell death to disease therapy

Nerve injury-induced protein 1 (NINJ1) was first identified as a membrane-bound adhesion molecule that participates in neural repair and tissue regeneration. In 2021, NINJ1 was identified as a major regulator and key execution molecule of plasma membrane rupture (PMR), a landmark discovery that overturned the traditional view of PMR as an entirely passive permeabilization event. NINJ1 plays critical roles in PMR, neural injury repair, and inflammatory response regulation, and is involved in the pathogenesis of inflammatory diseases, cardiovascular and cerebrovascular diseases, neurological disorders, and other pathological conditions with prominent dual regulatory functions. Targeting NINJ1-mediated PMR has emerged as a highly promising therapeutic strategy, and current interventions mainly focus on modulating NINJ1 activity, including inhibitory antibodies, small-molecule inhibitors, and functional peptides. This review systematically summarizes the structure, function, and molecular regulatory mechanisms of NINJ1, as well as its role in diseases. It also outlines the research progress of NINJ1-targeted drugs and discusses potential intervention strategies.