HK2 (hexokinase 2) catalyzes the phosphorylation of glucose to glucose-6-phosphate, mediating the initial rate-limiting step of glycolysis 1. Beyond its canonical metabolic function, HK2 localizes to mitochondria and mitochondria-associated membranes (MAMs) where it performs critical non-enzymatic roles in regulating autophagy, intracellular calcium flux, and inhibiting cell death 1. HK2 is significantly upregulated in multiple cancers including colorectal, gastric, and hepatocellular carcinoma, where it drives metabolic rewiring toward aerobic glycolysis and promotes tumorigenesis 234. In colorectal cancer, METTL3-mediated stabilization of HK2 mRNA through m6A modifications activates the glycolysis pathway 2. HK2 also plays pathological roles in inflammation and autoimmune disease; genetic deletion of HK2 in intestinal epithelial cells reduces colitis severity and epithelial cell death 5, while HK2 drives aggressive fibroblast-like synoviocyte functions in rheumatoid arthritis 6. Notably, HK2 suppression is essential during neuronal differentiation, as sustained HK2 expression causes neuronal cell death 7. These findings establish HK2 as a selective metabolic target with potential therapeutic applications in cancer, inflammatory diseases, and metabolic disorders.