Ketohexokinase (KHK) is the rate-limiting enzyme of fructose metabolism, catalyzing the phosphorylation of fructose to fructose-1-phosphate 1. This metabolic function is central to how dietary fructose is processed, particularly in the liver where KHK-C isoform is predominantly expressed 2. Mechanistically, KHK initiates fructolysis, which generates metabolic byproducts including lipid species such as lysophosphatidylcholines (LPCs) 2. When fructose is consumed excessively, KHK activity contributes to pathogenic pathways including de novo lipogenesis, impaired fatty acid oxidation, endoplasmic reticulum stress, and hepatic inflammation 1. Notably, fructose metabolism through KHK can directly impair hepatic insulin signaling by reducing insulin receptor expression and increasing protein-tyrosine phosphatase activity 1. KHK dysfunction has clinical relevance to metabolic disease. Knockdown of KHK increases hepatic insulin sensitivity 1, and pharmacological KHK inhibition decreases circulating lipid metabolites and prevents fructose-mediated tumor growth 2. The enzyme is also involved in cancer metabolism, where hepatocyte-derived LPCs produced via KHK-catalyzed fructose metabolism can enhance tumor growth through cell non-autonomous mechanisms 2. Elevated KHK expression occurs in certain cancers where it contributes to glycolytic reprogramming and immunosuppression 3.