Ketohexokinase (KHK) (KHK)

Ketohexokinase (KHK), also known as fructokinase, is the rate-limiting enzyme in fructose metabolism, catalyzing the phosphorylation of fructose to fructose-1-phosphate [2]. While primarily expressed in the liver, KHK-mediated fructose utilization in inflammatory cells, such as macrophages and monocytes, has been identified as a key driver of metabolic reprogramming toward a pro-inflammatory phenotype [1]. This process enhances the secretion of inflammatory cytokines and contributes to the pathogenesis of metabolic syndrome, non-alcoholic steatohepatitis (NASH), and cardiovascular diseases [2]. Therapeutic targeting of KHK with small-molecule inhibitors aims to block these downstream inflammatory and lipogenic pathways [3]. Clinical candidates like PF-06835919 have demonstrated the potential to reduce liver fat and systemic inflammatory markers, offering a novel approach to treating fructose-driven metabolic and inflammatory disorders [3].

Other names

FructokinaseHepatic fructokinaseKHK-AKHK-C

Ketohexokinase inhibitors competitively bind to the enzyme, preventing the phosphorylation of fructose to fructose-1-phosphate, which reduces downstream lipogenic and pro-inflammatory metabolic flux [2, 3].