ETV5 transcriptionally inhibits KIF23 to repress pyroptosis in aged mice with perioperative neurocognitive disorders

Caspase-3/gasdermin E (GSDME)-dependent Pyroptosis activation has emerged as a potential mechanism contributing to perioperative neurocognitive disorders (PND). Public transcriptome profiling identified the diminution of the transcription factor E-twenty-six variant 5 (ETV5) in the hippocampus of aged PND mice. This study intended to investigate the role of ETV5 and its target genes in the pathogenesis of PND. Bioinformatics analysis identified Kinesin family member 23 (KIF23) as a putative target gene of ETV5. The PND mouse model was established via laparotomy under isoflurane anesthesia after treatment with recombinant adeno-associated virus 9 (AAV9) to overexpress ETV5 and/or KIF23. HT22 neurons were transfected with either pcDNA3.1-ETV5 or siETV5, followed by treatment with isoflurane and lipopolysaccharide (Iso + LPS). Cognitive behavior, TUNEL staining, and pyroptosis-associated indicators were assessed. ETV5 mRNA and protein levels were significantly reduced in the mouse hippocampus following anesthesia and surgery. ETV5 overexpression attenuated cognitive impairment, enhanced antioxidant capacity, and hampered Caspase-3/GSDME-mediated Pyroptosis, which was neutralized by AAV9-KIF23. Under Iso + LPS conditions, ETV5 overexpression enhanced HT22 neuronal viability and antioxidant defense, suppressed the cleavage of Caspase-3 and GSDME, and diminished the release of IL-1β, IL-18, and LDH. Contrarily, its silencing had inverse effects on oxidative stress and Pyroptosis, which was abrogated by KIF23 knockdown. Mechanistically, ETV5 directly bound to the sequence spanning from 1 to 700 bp upstream of the KIF23 gene transcription initiation site and repressed its transcription. Our findings suggest that ETV5/KIF23 may represent a promising therapeutic target for PND.

ETV5; GSDME; KIF23; Perioperative neurocognitive disorders; Pyroptosis.