HK1 (hexokinase 1) is a crucial glycolytic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate, representing the initial and rate-limiting step of glycolysis 1. The enzyme contains a mitochondrial binding domain (MBD) that allows localization to the mitochondrial outer membrane, which is essential for proper cellular metabolism regulation 2. When HK1 dissociates from mitochondria and localizes to the cytosol, it dramatically alters cellular metabolism by reducing glycolytic flux below GAPDH and increasing glucose flux through the pentose phosphate pathway 2. This subcellular localization is critical in disease contexts: mitochondrial dissociation of HK1 in endothelial cells drives heart failure with preserved ejection fraction through increased protein O-GlcNAcylation 3, while cytosolic HK1 binding to S100A8/A9 results in GAPDH nitrosylation and metabolic reprogramming 2. Additionally, HK1 forms protective rings around mitochondria during energy stress, preventing mitochondrial fission by displacing Drp1 and maintaining mitochondrial connectivity 4. In pathological conditions, HK1 contributes to oligodendroglial inflammasome activation in Alzheimer's disease 1 and can be released from hepatic stellate cells via extracellular vesicles to promote hepatocellular carcinoma progression 5. The enzyme's expression is regulated by m6A methylation modifications under atheroprone flow conditions 6.