Hepatitis C Virus (HCV)-Mediated Activation of Hexokinase Domain-Containing Protein 1 (HKDC1) Promotes Hexokinase Activity and Metabolic Reprogramming.

Hepatitis C virus (HCV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC). One mechanism by which HCV promotes HCC is the remodeling of host cell metabolism; however, the molecular mediators of this process are not yet fully understood. In this study, we identified Hexokinase Domain-Containing Protein 1 (HKDC1) as a crucial effector that links HCV infection to glycolytic reprogramming in hepatoma cells. HCV-positive APC140 cells showed selective upregulation of HKDC1, accompanied by enhanced cytoplasmic localization of the protein. Moreover, these cells exhibited increased total hexokinase activity and elevated pyruvate and lactate production, while the classical hexokinases HK1, HK2, HK3, and HK4 remained unchanged. Depleting HKDC1 led to a reduction in hexokinase activity, glycolytic flux, and HCV subgenomic replicon-associated reporter activity, with no compensatory changes noted in other members of the hexokinase family. These findings indicate that HCV-induced HKDC1 creates a metabolic environment conducive to viral replication and may contribute to HCC development. Therefore, HKDC1 acts as a virus-responsive metabolic mediator that links chronic HCV infection to oncogenic metabolic reprogramming, positioning it as a potential therapeutic target in HCV-associated HCC.