HK2, also known as hexokinase-II, is a predominant isoform of hexokinases. Hexokinases catalyze the first step of glucose metabolism, phosphorylating glucose to glucose 6-phosphate (G6P). HK2 is crucial in insulin-sensitive tissues like heart, skeletal muscle, and adipose tissues, and is also associated with enhanced aerobic glycolysis (the Warburg effect) in many tumors [1,3,4,7,8]. It is involved in key pathways such as glycolysis and has been shown to have a role in autophagy, linking cellular metabolism to cell survival [1].

In cancer, deletion of HK2 in animal models has decreased cancer cell proliferation without explicit side effects, suggesting that targeting HK2 is a viable cancer therapy strategy [4]. In renal ischemia-reperfusion injury, knockout of HK2 attenuated the injury and inhibited glycolysis, with AST-120 alleviating the injury via suppressing HK2-mediated glycolysis [2]. In rheumatoid arthritis fibroblast-like synoviocytes, overexpression of a HK2 mutant lacking its mitochondrial binding motif reversed the invasive and migrative phenotype, indicating mitochondrial HK2 regulates the aggressive phenotype [5]. In neuropathic pain, selective ablation of Hk2 in microglia reduced microgliosis, and deletion of Hk2 in myeloid cells alleviated mechanical pain during the acute phase [6].

In conclusion, HK2 plays essential roles in multiple biological processes, especially in glucose metabolism-related pathways. Model-based research, particularly gene knockout in mouse models, has revealed its significance in diseases such as cancer, renal ischemia-reperfusion injury, rheumatoid arthritis, and neuropathic pain. Understanding HK2's functions through these models provides insights into potential therapeutic strategies for these conditions.