NINJ1: From an Adhesion Molecule to an Executor of Plasma Membrane Rupture

ABSTRACT: Nerve injury-induced protein 1 (NINJ1) was originally identified in 1996 as a homophilic adhesion molecule upregulated following nerve injury. For over two decades thereafter, research on NINJ1 primarily focused on areas such as nerve regeneration, immune cell migration, and inflammation regulation. In 2021, the discovery by Kayagaki’s group completely transformed the understanding of NINJ1—the protein was demonstrated to be a key executor of plasma membrane rupture (PMR) during lytic cell death, overturning the long-held view that PMR is a passive osmotic event. This finding rapidly sparked intensive research efforts in structural biology, cell death regulation, and therapeutic target development. This review is organized around the central scientific questions in NINJ1 research, systematically tracing the trajectory from molecular discovery, structural elucidation, and activation regulation to disease associations and therapeutic targeting. We critically analyze the logical relationships among different research avenues, discuss the underlying assumptions and limitations of current findings, and highlight the key knowledge gaps that remain in the field.