Lifting the veil on tumor metabolism: A GDH1-focused perspective

Tumors depend on glutamine for energy production, biosynthesis, and redox homeostasis. Glutamate dehydrogenase 1 (GDH1) primarily catalyzes the oxidative deamination of glutamate to α-ketoglutarate (α-KG) and ammonia, utilizing NAD⁺ or NADP⁺ as cofactors. α-KG is a tricarboxylic acid (TCA) cycle intermediate at the nexus of multiple metabolic pathways, fueling the TCA cycle for energy production or providing intermediates essential for lipid, amino acid, and nucleotide synthesis. Its derivatives, succinate and fumarate, function as oncometabolites that promote tumor progression through diverse mechanisms. Additionally, α-KG is an essential cofactor for α-KG-dependent dioxygenases (2-OGDDs), regulating epigenetic modifications that drive tumorigenesis. GDH1 may also catalyze the reductive amination of α-KG to glutamate under glutamine deprivation or hypoxic conditions. The roles of GDH1 in tumors are context-dependent, influencing progression through metabolic and epigenetic mechanisms. This review discusses GDH1's multifaceted functions and advances in targeting it for cancer therapy.