Spinal motor neuron degeneration after brachial plexus avulsion: mechanisms and therapeutic targets

Brachial plexus avulsion injury (BPAI) causes violent detachment of cervical ventral roots and rapid degeneration of spinal motor neurons (SMNs), driven by abrupt energy failure, axonal disconnection, and a rapidly escalating neuroinflammatory microenvironment. Current evidence demonstrates that SMN loss arises from the coordinated activation of multiple programmed cell death (PCD) pathways-including apoptosis, necroptosis, pyroptosis, ferroptosis, and impaired autophagy-regulated by oxidative stress, mitochondrial dysfunction, calcium overload, iron dyshomeostasis, and inflammasome activation. Crosstalk among these pathways, amplified by microglial priming, macrophage infiltration, and astrocytic reactivity, forms a self-propagating neurodegenerative network extending beyond the avulsion site. This review integrates recent mechanistic advances, highlighting key regulators such as the METTL14-EEF1A2 m 6 A axis, RIPK1/RIPK3/MLKL necrosome, NLRP3-GSDMD pyroptotic signaling, GPX4-dependent ferroptosis, and AR-SIRT1-AMPK-mTOR-mediated autophagy disruption. We further summarize emerging interventions-including PCD-targeted inhibitors, immunomodulatory therapies, biomaterial-based delivery systems, gene therapy, and neural organoid transplantation-toward precision neuroprotection and improved functional recovery after BPAI.