Integrated Necroptosis Within Programmed Cell Death in Traumatic Brain Injury.

Traumatic brain injury (TBI), a major global public health burden, is characterized by complex pathophysiology involving primary and secondary injuries, with programmed cell death (PCD) pathways significantly impacting neuronal damage and neurological dysfunction. Substantial evidence over time highlights necroptosis-a caspase-independent, inflammatory form of PCD mediated by RIPK1/RIPK3/MLKL-as a key driver of secondary injury after TBI. However, the dynamic interplay between necroptosis and other PCD pathways after TBI remains poorly understood. In this review, we systematically describe the mechanisms involving necroptosis in TBI and its potential therapeutic targets, while delving into the interplay and regulatory relationships between necroptosis and other PCD pathways, including apoptosis, autophagy, pyroptosis, and ferroptosis. Future investigations and the formulation of therapeutic approaches for TBI should comprehensively consider the complex characteristics of necroptosis and its interplay with other pathways.