Notch Signaling in Spinal Cord Injury: Mechanistic Insights and Therapeutic Perspectives.

Spinal cord injury (SCI) is a severe central nervous system injury that often results in persistent motor, sensory, and autonomic dysfunction below the level of injury. Following the primary insult, secondary pathological processes, including inflammation, oxidative stress, neuronal apoptosis, and persistent reactive astrogliosis, further aggravate tissue damage and hinder repair. Notch signaling is a highly conserved cell-cell communication pathway that regulates inflammatory responses, oxidative stress, cell survival, neuronal differentiation, and vascular remodeling. Increasing evidence indicates that Notch signaling participates in both secondary injury and tissue repair after SCI. However, its biological effects vary according to the responding cell type, receptor-ligand interaction, stage of injury, and timing and duration of pathway modulation. This review outlines the molecular basis of Notch signaling and examines its roles in secondary injury, neural repair, and vascular remodeling after SCI. It also evaluates pharmacological, physical, stem cell-based, and gene-regulatory strategies that modulate this pathway. Current evidence supports considering Notch signaling a context-dependent therapeutic target rather than a pathway that should be uniformly activated or inhibited. Therefore, future therapeutic strategies should incorporate cell-specific targeting, clearly defined treatment windows, and localized delivery approaches to preserve beneficial Notch activity while limiting harmful responses.