Hexokinase 2 reduces aberrant neurogenesis by promoting TREM2-mediated microglial phagocytosis in epilepsy mouse model

Hexokinase 2 (HK2), a rate-limiting glycolytic enzyme, regulates inflammatory signaling and inflammasome activation in multiple neurological diseases; however, its function in epilepsy remains largely unexplored. Here, we show that HK2 expression is markedly upregulated in the brains of pilocarpine-induced epileptic mouse model. Pharmacological inhibition or microglia-specific HK2 deletion inhibited microglia activation and enhanced microglial phagocytosis, and subsequently decreased both the frequency and cumulative duration of hippocampal paroxysmal discharges during the chronic phase of spontaneous epilepsy. HK2 deficiency significantly increased the expression of the microglial activation marker CD68, and elevated levels of the phagocytic receptor TREM2. TREM2 inhibitor TREM2-IN-1 (OPA) inhibited HK2 deletion-induced microglial phagocytosis and chronic recurrent seizures. Overall, these findings indicate that microglial HK2-dependent glycolytic reprogramming plays a key role in epilepsy progression and highlight HK2 as a potential therapeutic target.