Metabolic Remodeling During the Early Phase of Spontaneous Seizure Emergence Highlights Hexosamine Biosynthetic Pathway Dysregulation in Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is a prevalent form of drug‐resistant epilepsy characterized by profound biochemical alterations. Emerging evidence suggests that metabolic dysregulation plays a crucial role in the development of TLE. In this study, we employed a kainic acid‐induced mouse model of TLE to investigate metabolic remodeling and key regulatory pathways at Day 14 post–status epilepticus, a time point within early epilepsy, corresponding to the early phase of spontaneous seizure emergence during epileptogenic progression. Liquid chromatography–mass spectrometry‐based proteomics and metabolomics analyses were conducted on hippocampal and serum samples to identify and quantify differentially expressed metabolites and proteins. Joint pathway analysis revealed substantial metabolic reprogramming, with consistent upregulation of the hexosamine biosynthetic pathway (HBP), converging on amino sugar and nucleotide sugar metabolism. Western blotting, immunohistochemistry, and targeted metabolite quantification further validated the elevation of key HBP components in the hippocampus, supporting HBP activation as a hallmark of metabolic remodeling during early seizure emergence. These findings provide novel insight into the metabolic landscape of epileptogenesis and highlight HBP‐related alterations as potential contributors to seizure development and promising therapeutic targets.