The KHK gene encodes ketohexokinase, an enzyme mainly expressed in the liver, kidneys, and small intestine, and plays a crucial role in fructose metabolism. KHK catalyzes the phosphorylation of fructose into fructose-1-phosphate, which is the first step in the fructose metabolic pathway, enabling its conversion into intermediate products that can enter the glycolytic or gluconeogenic pathways. This gene generates two isoforms (KHK-A and KHK-C). Among them, KHK-C has higher catalytic activity and is mainly expressed in the liver, while KHK-A is widely distributed in various tissues, but its function is not fully understood. The expression and activity of KHK are closely related to fructose intake. Excessive fructose intake will lead to the upregulation of KHK activity, which triggers metabolic disorders, such as metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and obesity ^[1]. The excessive activation of KHK-C is closely associated with fructose-induced metabolic dysfunction, and blocking KHK-C can significantly ameliorate metabolic abnormalities in fructose-sensitive mice ^[2]. In addition, fructose metabolism may play an important role in cancer and other proliferative diseases, providing signaling cues that sustain the proliferation of cancer cells. Many cancer cells overexpress KHK. Moreover, the genetic disorder (essential fructosuria) caused by loss-of-function mutations in KHK is clinically asymptomatic and harmless, which further supports the view that inhibiting KHK in cancer patients may be well tolerated ^[3]. Therefore, KHK has emerged as a potential target for treating metabolic diseases and cancer. Inhibitors targeting KHK are currently under development and have shown the potential to improve metabolic syndrome and inhibit tumor progression.

The B6-hKHK mice are a humanized model constructed through gene editing technology, in which the sequence of the mouse Khk gene is replaced in situ with the corresponding sequence of the human KHK gene. Homozygous B6-hKHK mice are viable and fertile. This model can be used for the study of the pathological mechanisms and treatment methods of metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), insulin resistance, and obesity, as well as cancer. It can also be applied to the screening, research and development, and safety evaluation of KHK-targeted drugs.