Khk, also known as ketohexokinase, is the primary enzyme for fructose metabolism. It catalyzes the first step of fructolysis, phosphorylating fructose to fructose-1-phosphate. This process is crucial in various metabolic pathways, including de novo lipogenesis (DNL), fatty acid oxidation, and glycolysis, and is of great biological importance in the context of metabolic diseases and cancer [1,2,3,4,5,6]. Genetic models, such as KO/CKO mouse models, have been valuable in studying Khk's function.

In animal models, inhibition of Khk using a small molecule inhibitor (PF-06835919) reversed fructose-induced metabolic dysfunction, including insulin resistance, hypertriglyceridemia, and hepatic steatosis. This coincided with reduced DNL and inactivation of the lipogenic transcription factor ChREBP [2]. In mice, a liver-specific knockdown of Khk-C improved the NAFLD activity score and had a profound effect on the hepatic transcriptome when consuming fructose with a high-fat diet [4]. Also, pharmacological inhibition of ketohexokinase decreased circulating lysophosphatidylcholines (LPCs) and prevented fructose-mediated tumour growth in vivo, as cancer cells utilized hepatocyte-derived LPCs for growth [7].

In conclusion, Khk plays a key role in fructose metabolism and is involved in multiple biological processes related to metabolic diseases and cancer. Studies using Khk KO/CKO mouse models have revealed its significance in conditions such as metabolic syndrome-related liver diseases and tumour growth, providing insights into potential therapeutic strategies targeting Khk in these disease areas.