<scp>NINJ1</scp> ‐Mediated Plasma Membrane Rupture in Lytic Cell Death: Mechanisms, Consequences, and Context

Lytic cell death has long been interpreted as a terminal consequence of inflammasome activation, gasdermin cleavage, and osmotic membrane failure. Recent evidence supports a more differentiated cellular model in which early membrane permeabilization and terminal plasma membrane rupture are distinct events. However, these processes are still frequently treated as a single continuum, and a unifying framework that separates and integrates them across lytic death pathways is lacking. Within this revised framework, ninjurin 1 (NINJ1) has emerged as the best-supported mediator of plasma membrane rupture during terminal lytic cell death. Studies in pyroptosis, post-apoptotic lysis, ferroptosis, and related necrotic settings indicate that NINJ1 is not required for inflammasome assembly, gasdermin processing, or early cytokine release, but is crucial for terminal membrane disruption and release of large intracellular contents. Structural, biochemical, and imaging data further show that NINJ1 transitions from an autoinhibited membrane-associated state to higher order assemblies that destabilize or excise plasma membrane regions. These findings support a staged model of lytic death in which gasdermin pores establish a permeabilized state, whereas NINJ1 drives the final disintegration of the cell surface. Across these contexts, NINJ1 is best viewed as a convergent membrane-rupture effector that defines a distinct downstream layer of lytic cell death rather than a pathway-restricted component. This distinction has important implications for understanding how membrane rupture shapes cell morphology, extracellular release patterns, and tissue injury. By integrating evidence across lytic death programs, this review advances a unified framework in which permeabilization and terminal rupture are mechanistically separable, differentially regulated processes.