Hexokinase domain containing protein 1 (HKDC1)

Hexokinase domain containing protein 1 (HKDC1) is a recently identified fifth isoform of the hexokinase enzyme family, encoded on chromosome 10 in humans. HKDC1 shares significant sequence homology with classical hexokinases (such as HK1) and possesses intrinsic hexokinase activity, catalyzing the rate-limiting and first obligatory step of glucose metabolism: converting glucose to glucose-6-phosphate in an ATP-dependent reaction. The enzyme is broadly expressed, with particularly high expression in the liver, certain tumors, and tissues necessary for maternal–fetal energy exchange. HKDC1 plays critical roles in regulating cellular energy metabolism and homeostasis, especially during states of metabolic stress such as pregnancy, cancer, and aging. It is implicated in the adaptive integrated cellular stress response and is upregulated during lysosomal and mitochondrial damage, where it governs calcium transfer and cellular clearance mechanisms. In cancer, notably liver and gastric cancer, HKDC1 is dramatically overexpressed and supports tumorigenesis, metabolic reprogramming, proliferation, migration, epithelial–mesenchymal transition, and chemoresistance. Genetic variants in HKDC1 are associated with glycemic traits, including gestational hyperglycemia and type 2 diabetes risk, indicating its clinical relevance in metabolic diseases. HKDC1’s functional importance and tissue specificity suggest it is a promising, albeit complex, therapeutic target—a subject of current research in oncology and metabolic disorders.

Other names

Hexokinase domain containing protein 1HKDC1RP92

Chemoresistance mediated via upregulation of glycolysis and activation of the NF-κB pathway. Modulation of glucose flux and metabolic reprogramming (targeting HKDC1–mitochondria interaction). Potentially targeted to impair cancer cell energy metabolism by disrupting mitochondrial and glycolytic functions.