Enhanced Glycolysis‐Driven Histone H3K18 Lactylation Regulates Epileptogenesis by Modulating the E3 Ubiquitin Ligase COP1

ABSTRACT Metabolic reprogramming is increasingly implicated in epilepsy, yet the mechanisms linking metabolic shifts to neuronal hyperexcitability remain elusive. Here, we identify lactate‐driven histone H3 lysine 18 lactylation (H3K18la), a novel post‐translational modification, as a critical epigenetic regulator of seizure susceptibility. Using kainic acid (KA)‐induced epilepsy models, we demonstrate that enhanced glycolytic flux through pyruvate kinase M2 (PKM2) generates excess lactate, driving robust H3K18la elevation in neurons during acute epileptogenesis. Chromatin immunoprecipitation sequencing (ChIP‐seq) analysis revealed that this epigenetic mark promotes transcriptional upregulation of the E3 ubiquitin ligase Cop1 . COP1 subsequently promotes K48‐linked polyubiquitination and proteasomal degradation of the γ‐aminobutyric acid type A (GABA A ) receptor β2 subunit (GABA A Rβ2), reducing inhibitory synaptic transmission, and heightening seizure susceptibility. Pharmacological or genetic targeting of PKM2 or genetic knockout of Cop1 reversed these effects and conferred robust seizure protection. Our findings reveal a pathogenic metabolic‐epigenetic‐proteostatic pathway in epilepsy, offering new therapeutic targets for restoring brain metabolic and electrical homeostasis.