The role of NINJ1 in diseases

Nerve injury-induced protein 1 (NINJ1) is a multifunctional membrane protein historically studied for its roles in nerve regeneration and cell adhesion. A groundbreaking study fundamentally revised our understanding by demonstrating that NINJ1 acts as the active executor of plasma membrane rupture in lytic cell death pathways such as pyroptosis and ferroptosis, establishing this final step as a biologically regulated process. Recent structural insights now reveal that NINJ1 adopts distinct molecular forms-including the full-length monomer, a soluble fragment, and a membrane-rupturing oligomer-which dictate its functional roles in adhesion, chemotaxis, and cell lysis. This revised understanding calls for a systematic integration of previous observations, particularly given NINJ1's context-dependent and often contradictory roles in inflammation, cancer, and tissue injury. Here, we review the structural basis of NINJ1 function, its pathological implications, and propose a unified structure-function model to reconcile its diverse phenotypes and bridge its traditional roles with its newly identified function in membrane rupture.