Nuclear hexokinase 2 couples hyperglycemia to MYC-driven glycolytic and stemness programs in bladder cancer

Abstract Hyperglycemia is common in patients with bladder cancer and has been implicated in disease progression, yet the molecular link between a high-glucose milieu and tumor aggressiveness remains poorly defined. Here we identify a noncanonical, nuclear role of hexokinase 2 (HK2) that couples systemic hyperglycemia to MYC-driven glycolysis and stemness in bladder cancer. High glucose promotes nuclear translocation of HK2, where HK2 directly binds the central region of MYC to form a functional transcriptional complex. This HK2–MYC complex occupies the promoters of key glycolytic genes, including HK2 and lactate dehydrogenase A (LDHA), and synergistically activates their transcription, thereby enhancing glycolytic flux and upregulating stemness-associated markers such as CD44. Genetic or pharmacologic inhibition of HK2 attenuates high glucose–induced proliferation, colony formation, and glycolytic reprogramming in vitro. In mouse models, hyperglycemia accelerates tumor growth, whereas treatment with the HK2 inhibitor lonidamine mitigates tumor progression in the hyperglycemic setting. Analysis of human bladder cancer specimens reveals that HK2 expression positively correlates with MYC and LDHA levels and associates with worse patient survival, particularly in patients with hyperglycemia. Collectively, our findings uncover a metabolic–transcriptional coupling pathway in which nuclear HK2 functions as a MYC cofactor to drive glycolysis and stemness under high-glucose conditions, and they suggest that targeting HK2 may represent a rational therapeutic strategy for patients with bladder cancer and coexisting hyperglycemia or diabetes.