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

## TL;DR

This paper reviews how spinal motor neurons die after brachial plexus avulsion injury and explores new therapeutic strategies to prevent this degeneration.

## Contribution

The paper integrates recent findings on multiple programmed cell death pathways and highlights novel therapeutic targets for spinal motor neuron protection.

## Key findings

- Spinal motor neuron degeneration after BPAI involves multiple PCD pathways like apoptosis, necroptosis, and pyroptosis.
- Key regulators include the METTL14-EEF1A2 m6A axis and the RIPK1/RIPK3/MLKL necrosome.
- Emerging therapies target PCD pathways and neuroinflammation to improve recovery after BPAI.

## Abstract

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 m6A 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.