D2hgdh-KO Mouse

D2hgdh, encoding D-2-hydroxyglutarate dehydrogenase, is an inducible enzyme that converts D-2-hydroxyglutarate (D2HG) into the endogenous metabolite 2-oxoglutarate [1]. It is involved in regulating cellular energy and biosynthetic intermediates, and is associated with pathways related to α-ketoglutarate-dependent dioxygenases, which are implicated in histone and DNA methylation, and HIF1α hydroxylation [2].

In the context of immunotherapy, D2HG impairs CD8 T lymphocyte function, but D2HGDH-modified CAR-T cells show distinct phenotypes. D2HGDH-over-expression (OE) CAR-T cells can utilize D2HG catabolism to enhance T cell expansion, function, and anti-tumor effectiveness in an immunosuppressive microenvironment [1]. In diffuse large B-cell lymphoma, D2HGDH mutants are enzymatically inert, while wild-type D2HGDH elevates α-ketoglutarate levels, influencing epigenetic modifications [2]. Downregulating D2HGDH in neurons reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio, elevates reactive oxygen species (ROS) levels, affects synaptic function, and enhances susceptibility to epilepsy [3].

In conclusion, D2hgdh is crucial for D2HG catabolism and regulation of α-ketoglutarate levels, influencing multiple biological processes. Studies on D2hgdh-modified CAR-T cells, its mutants in lymphoma, and its downregulation in epilepsy-related neurons highlight its significance in immunotherapy, cancer, and epilepsy research, providing potential therapeutic targets for these diseases.