NEMO‐Binding Domain/IKKγ Inhibitory Peptide Alleviates Neuronal Pyroptosis in Spinal Cord Injury by Inhibiting ASMase‐Induced Lysosome Membrane Permeabilization

A short peptide termed NEMO‐binding domain (NBD) peptide has an inhibitory effect on nuclear factor kappa‐B (NF‐κB). Despite its efficacy in inhibiting inflammatory responses, the precise neuroprotective mechanisms of NBD peptide in spinal cord injury (SCI) remain unclear. This study aims to determine whether the pyroptosis‐related aspects involved in the neuroprotective effects of NBD peptide post‐SCI.Using RNA sequencing, the molecular mechanisms of NBD peptide in SCI are explored. The evaluation of functional recovery is performed using the Basso mouse scale, Nissl staining, footprint analysis, Masson's trichrome staining, and HE staining. Western blotting, enzyme‐linked immunosorbent assays, and immunofluorescence assays are used to examine pyroptosis, autophagy, lysosomal membrane permeabilization (LMP), acid sphingomyelinase (ASMase), and the NF‐κB/p38‐MAPK related signaling pathway.NBD peptide mitigated glial scar formation, reduced motor neuron death, and enhanced functional recovery in SCI mice. Additionally, NBD peptide inhibits pyroptosis, ameliorate LMP‐induced autophagy flux disorder in neuron post‐SCI. Mechanistically, NBD peptide alleviates LMP and subsequently enhances autophagy by inhibiting ASMase through the NF‐κB/p38‐MAPK/Elk‐1/Egr‐1 signaling cascade, thereby mitigating neuronal death. NBD peptide contributes to functional restoration by suppressing ASMase‐mediated LMP and autophagy depression, and inhibiting pyroptosis in neuron following SCI, which may have potential clinical application value. Spinal cord injury (SCI) is a serious and potentially fatal disease, but there is currently no effective treatment for SCI. The current study shows that NBD peptide contributes to functional restoration by suppressing ASMase‐mediated LMP and autophagy depression, and inhibiting pyroptosis in neuron following SCI. These findings indicate that NBD peptide may have potential clinical application value.