KHK-C

Ketohexokinase C (KHK-C) is the high-affinity fructokinase isoform that catalyzes the phosphorylation of fructose to fructose-1-phosphate, the first and rate-limiting step of fructose metabolism in metabolic tissues including the liver, kidney, and intestine^[1][2][3]. KHK-C drives cellular fructolysis and enables fructose-derived carbon flux into downstream metabolic pathways through the production of fructose-1-phosphate and its subsequent conversion by aldolase B^[1][4]. Mechanistically, fructose metabolism mediated by KHK-C bypasses the major phosphofructokinase regulatory checkpoint of glycolysis, thereby facilitating rapid fructose utilization and metabolic remodeling^[5][6]. In metabolic disease models, increased fructose metabolism through KHK-C has been associated with insulin resistance, de novo lipogenesis, hepatic steatosis, endoplasmic reticulum stress, and broader metabolic dysfunction induced by excessive fructose exposure^[4][7][8]. Genetic or experimental suppression of KHK reduces fructose metabolism and ameliorates pathological metabolic phenotypes in models of fructose-driven liver disease and obesity-associated metabolic dysfunction^[7][8][9]. Compared with the ubiquitously expressed KHK-A isoform, KHK-C exhibits substantially higher affinity for fructose and is considered the principal isoform responsible for physiological fructose clearance and tissue-specific fructose metabolism^[1][2][10]. This functional distinction is supported by evidence showing that KHK-C expression is enriched in major fructose-metabolizing organs, whereas KHK-A displays lower fructose affinity and broader tissue distribution^[1][2][10]. For experimental applications, pharmacological KHK inhibitors, including PF-06835919, have been developed to block fructose metabolism and are widely used to investigate the contribution of KHK-dependent fructolysis to metabolic disease pathogenesis^[4][11].