D2HGDH (D-2-hydroxyglutarate dehydrogenase) is a mitochondrial enzyme that catalyzes the oxidation of D-2-hydroxyglutarate (D-2HG) to α-ketoglutarate (α-KG), playing a crucial role in cellular metabolism and epigenetic regulation 1. The enzyme also oxidizes other D-2-hydroxyacids including D-malate and D-lactate, with highest activity toward D-2HG and D-malate 2. D2HGDH functions as a key regulator of cellular homeostasis by modulating α-KG-dependent dioxygenases that control histone and DNA methylation, as well as HIF1α hydroxylation 1. The enzyme positively modulates mitochondrial IDH activity and induces IDH2 expression, thereby elevating α-KG levels 1. MYC directly regulates D2HGDH transcription, linking the enzyme to broader metabolic control of the epigenome and epitranscriptome 3. Disease relevance includes D-2-hydroxyglutaric aciduria 1, caused by germline D2HGDH mutations 4. In cancer, D2HGDH expression correlates with poor prognosis in breast carcinoma and serves as a prognostic marker 5. Decreased D2HGDH expression in ulcerative colitis patients correlates with progression to colorectal cancer, with elevated D-2HG levels driving tumorigenesis 6. Additionally, D2HGDH deficiency enhances seizure susceptibility through oxidative stress mechanisms involving GSH/ROS pathways 7.