D2HGDH is a mitochondrial enzyme that catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate, with secondary activity toward D-malate but weak activity toward D-lactate. By converting D-2-HG, a metabolite that accumulates in IDH1/2-mutant cancers, D2HGDH maintains alpha-ketoglutarate pools available for alpha-ketoglutarate-dependent dioxygenases, which regulate histone methylation, DNA methylation, and HIF-1α hydroxylation 1. D2HGDH expression is induced by MYC and influences the epigenome and epitranscriptome through effects on TET enzymes and RNA demethylases 2. Loss of D2HGDH function is associated with D-2-hydroxyglutaric aciduria, a neurometabolic disorder; in experimental models, D2HGDH knockdown increases seizure susceptibility by elevating reactive oxygen species and disrupting glutathione homeostasis 3. In cancer, D2HGDH overexpression promotes breast carcinoma proliferation and is an independent predictor of worse prognosis, while D2HGDH loss in colitis-associated colon cancer permits D-2-HG accumulation that drives progression to cancer 4, 5. D2HGDH-overexpressing CAR-T cells show enhanced anti-tumor efficacy against IDH1-mutant leukemia in high-D2HG microenvironments 6.