SNAP25 ameliorates postoperative cognitive dysfunction by facilitating PINK1-dependent mitophagy and impeding caspase-3/GSDME-dependent pyroptosis

Insufficient PTEN-induced kinase 1 (PINK1)-mediated mitophagy and activation of caspase-3/gasdermin E (GSDME)-dependent pyroptosis constitute the potential etiology of postoperative cognitive dysfunction (POCD), a severe neurological complication characterized by learning and memory deficits. Synaptosomal-Associated Protein 25 (SNAP25), a well-defined presynaptic protein that mediates the fusion between synaptic vesicles and plasma membrane, is crucial in autophagy and the trafficking of extracellular proteins to the mitochondria. We investigated whether SNAP25 regulates POCD via mitophagy and pyroptosis. SNAP25 downregulation was observed in the hippocampi of rats undergoing isoflurane anesthesia and laparotomy. SNAP25 silencing restrained PINK1-mediated mitophagy and promoted reactive oxygen species (ROS) production and caspase-3/GSDME-dependent pyroptosis in isoflurane (Iso) + lipopolysaccharide (LPS)-primed SH-SY5Y cells. SNAP25 depletion also destabilized PINK1 on the outer membrane of the mitochondria and blocked Parkin translocation to the mitochondria. In contrast, SNAP25 overexpression alleviated POCD and Iso + LPS-induced defective mitophagy and pyroptosis, which was reversed by PINK1 knockdown. These findings suggest that SNAP25 exerts neuroprotective effects against POCD by boosting PINK1-dependent mitophagy and hindering caspase-3/GSDME-dependent pyroptosis, providing a novel option for the management of POCD.