KIF23 inhibition protects against perioperative neurocognitive disorders by hindering ROS/caspase-3/GSDME-mediated pyroptosis

The activation of caspase-3 and gasdermin E (GSDME)-mediated pyroptosis is a key driver of perioperative neurocognitive disorders (PND). Kinesin family member 23 (KIF23), a constituent of the kinesin superfamily of microtubule-associated motor proteins, governs NLRP3 inflammasome-mediated pyroptosis and is essential for dendritic differentiation and development. This study sought to ascertain whether KIF23 influences PND by affecting caspase-3/GSDME-dependent pyroptosis. The PND mouse model was established through laparotomy under isoflurane (Iso) anesthesia following recombinant adeno-associated virus 9 (AAV9)-mediated knockdown of KIF23, with or without the intraperitoneal administration of the caspase-3 agonist Raptinal. HT22 cells were transfected with either pcDNA3.1-KIF23 or siKIF23, followed by exposure to Iso and lipopolysaccharide (LPS). Cognitive performance, TUNEL staining, and pyroptosis-related parameters were assessed. KIF23 protein was upregulated in the hippocampus of aged mice following anesthesia and surgery. AAV9-shKIF23 ameliorated postoperative memory decline, suppressed reactive oxygen species (ROS) production and diminished the levels of cleaved caspase-3, N-GSDME, IL-1β and IL-18, which were reversed by Raptinal. KIF23 silencing enhanced neuronal viability and antioxidant capacity, blocked the cleavage of caspase-3 and N-GSDME, and repressed the release of IL-1β, IL-18, and LDH. Conversely, KIF23 overexpression exerted opposing effects on pyroptosis in response to Iso + LPS, which was abrogated by the caspase-3 inhibitor Ac-DEVD-CHO. These findings suggest that KIF23 could serve as a promising therapeutic target for PND through its positive modulation of pyroptosis.