Digging deeper into NINJ1: its multifaceted role in central nervous system diseases.

Ninjurin1 (NINJ1) is a cell-surface molecule that has gained considerable attention for its role in mediating plasma membrane rupture (PMR). Originally identified as an adhesion molecule induced after nerve injury, NINJ1 is now recognized as a common terminal executor of PMR across multiple forms of lytic cell death, including pyroptosis, necroptosis, and ferroptosis. This function positions NINJ1 as a key link between cell death and inflammatory activation. However, the precise role of NINJ1 in the central nervous system (CNS) remains unclear. This review systematically outlines the molecular structure, expression, activation, and regulation of NINJ1, with a focus on its multifaceted roles in CNS disorders, including multiple sclerosis, ischemic stroke, traumatic brain injury, spinal cord injury, neuropsychiatric disorders and neurodegenerative diseases. We also highlight critical knowledge gaps, particularly regarding cell type-specific functions in the CNS. Finally, we evaluate therapeutic strategies targeting NINJ1 (including monoclonal antibodies, functional peptides, and small-molecule inhibitors) and their potential applications in neurological diseases. By integrating current evidence and identifying unresolved questions, this review aims to provide a foundation for future mechanistic and translational studies of NINJ1 in the CNS.