D2hgdh, encoding D-2-hydroxyglutarate dehydrogenase, is an inducible enzyme. It converts D-2-hydroxyglutarate (D2HG) into 2-oxoglutarate, playing a role in the interconversion of metabolites within metabolic pathways. This conversion is crucial as D2HG has been implicated in various cancers and neurometabolic disorders, highlighting the importance of D2hgdh in maintaining cellular homeostasis [1,2,4,5,6,7].

In the context of immunotherapy, D2HG limits its effect. D2hgdh-modified CAR-T cells show distinct phenotypes. D2hgdh knockout (KO) CAR-T cells have decreased central memory cell differentiation and cytokine production, while D2hgdh over-expression (OE) CAR-T cells have enhanced anti-tumor activity against NALM6 cancer cells in a high-D2HG environment. In vivo xenograft experiments confirmed that D2hgdh-OE CAR-T cells reduce serum D2HG and improve the survival of mice with NALM6 cancer cells [1]. In diffuse large B-cell lymphoma, D2hgdh mutants are enzymatically inert, while wild-type D2hgdh elevates α-ketoglutarate levels, influencing histone and DNA methylation, and HIF1α hydroxylation. It also regulates IDH2 activity, with genetic depletion of IDH2 abrogating D2hgdh effects [2]. Downregulating D2hgdh in a mouse model enhances susceptibility to epilepsy, affecting synaptic function by regulating ROS production [3]. In colitis-associated colon cancer (CAC), decreased colonic D2hgdh expression is observed in ulcerative colitis patients who progress to cancer, and urine D2HG and tissue D2hgdh expression can be used as biomarkers [7].

In conclusion, D2hgdh is essential for the catabolism of D2HG, which impacts multiple biological processes and disease conditions. Studies using gene knockout and other genetic models, especially in immunotherapy-related cancer, epilepsy, and CAC research, have significantly enhanced our understanding of D2hgdh's role in these diseases, providing potential therapeutic targets and biomarkers.