D2HGDH and epilepsy: To elucidate the potential role and mechanism of D2HGDH in epilepsy, this study 1) determined the localization of D2HGDH in human and C57BL/6J brain tissues; 2) investigated the potential involvement of D2HGDH in epilepsy models, including kainic acid (KA) and pentylenetetrazol (PTZ) models; 3) assessed the functional effects of D2HGDH on hippocampal neurons in C57BL/6J mice; and 4) used metabolomics, proteomics, and gene set enrichment analysis (GSEA) to explore potential downstream pathways following downregulation of D2HGDH.