D2HG

D-2-hydroxyglutarate (D-2-HG) is a metabolite that accumulates in cells when isocitrate dehydrogenase (IDH) enzymes 1 and 2 harbor hotspot mutations. These mutations confer a neomorphic activity that converts α-ketoglutarate (α-KG) to D-2-HG, leading to elevated intracellular levels. D-2-HG is one of two enantiomers of 2-hydroxyglutarate; the other enantiomer, L-2-HG, arises from different metabolic pathways and is linked to distinct conditions.

Mechanistically, D-2-HG inhibits α-KG–dependent dioxygenases, including TET family DNA demethylases and JmjC-domain–containing histone demethylases. This inhibition promotes genome-wide DNA and histone hypermethylation, contributing to an epigenetic landscape associated with impaired cellular differentiation and tumorigenesis. In gliomas, this hypermethylation phenotype is often referred to as G-CIMP.

Clinically, D-2-HG serves as a biomarker for IDH-mutant cancers. It can be detected in tumor tissue and, in some contexts, in body fluids such as plasma or cerebrospinal fluid. Measurement methods include mass spectrometry and, in tumors, magnetic resonance spectroscopy for in vivo assessment.

Therapeutically, reducing D-2-HG production through targeted IDH inhibitors has shown clinical benefit in IDH-mutant cancers. Notable approved agents include ivosidenib for IDH1-mutated acute myeloid leukemia (AML) and enasidenib for IDH2-mutated AML, with ongoing trials exploring use in other IDH-mutant malignancies, including gliomas. The link between D-2-HG reduction and restoration of differentiation underpins these therapeutic strategies.