Macamide B alleviates neuronal pyroptosis in spinal cord injury by activating acid ceramidase to inhibit lysosome membrane permeabilization

Abstract Spinal cord injury is a devastating neurological disorder that causes severe and persistent functional deficits, for which effective pharmacological treatments remain limited. Acid ceramidase is a key lysosomal hydrolase involved in sphingolipid metabolism and has been implicated in cellular homeostasis and central nervous system disorders. However, its role in lysosomal membrane permeabilization and autophagic flux following spinal cord injury remains unclear. In this study, virtual screening identified macamide B as a potential activator of acid ceramidase, and its neuroprotective effects and underlying mechanisms were investigated in a mouse model of spinal cord injury. We found that macamide B treatment significantly reduced glial scar formation and motor neuron loss, thereby improving functional recovery after spinal cord injury. Moreover, macamide B suppressed neuronal pyroptosis and restored impaired autophagic flux associated with lysosomal membrane permeabilization. Mechanistically, macamide B activated acid ceramidase through the extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway, thereby alleviating lysosomal membrane permeabilization and restoring autophagic flux, ultimately attenuating neuronal pyroptosis and neuronal loss. Collectively, these findings reveal an extracellular signal-regulated kinase/mitogen-activated protein kinase/acid ceramidase-mediated mechanism underlying the neuroprotective effects of macamide B after spinal cord injury and suggest that pharmacological activation of acid ceramidase may represent a promising therapeutic strategy for promoting neurological recovery following spinal cord injury.