Further experiments demonstrated that OTUD1-mediated K63-linked ubiquitination on HK2 triggers mitochondrial HK2-VDAC1 dissociation, initiating VDAC1 oligomerization-mediated mtDNA release that activates NLRP3 inflammasome-driven microglia pyroptosis and pro-inflammatory cytokine release, ultimately leading to neuronal damage, synaptic dysfunction, and cognitive deficits in SAE, establishing OTUD1-regulated pyroptosis as a central pathogenic mechanism. This evidence concerns the gene HK2 and Cognitive impairment.