Ketohexokinase: A central mediator of fructose-associated pathogenesis and promising therapeutic target

Accumulating preclinical and clinical evidence identifies Ketohexokinase (KHK), the initial enzyme of fructose catabolism, as a core mediator of fructose-driven pathogenesis, positioning pharmacological KHK inhibition as a promising therapeutic strategy for fructose-associated disorders. Functionally divergent KHK isoforms arise from alternative splicing. The high-activity KHK-C, predominantly expressed in the liver, kidney, and small intestine, drives fructose-related metabolic pathologies, including metabolic dysfunction-associated steatotic liver disease, diabetic kidney disease, and obesity. In contrast, the ubiquitously expressed low-activity KHK-A mediates tumor metabolic reprogramming, proliferation, and metastasis via both metabolic and non-canonical protein kinase activities. KHK expression and isoform switching are dynamically regulated by multiple upstream factors, including dietary composition, the uric acid/ChREBP transcriptional axis, hypoxia-inducible factors, and medium-chain fatty acids, with pleiotropic KHK functions extending beyond metabolic regulation to cardiac homeostasis, bone development, and neurocognitive processes. Translational development of KHK inhibitors has achieved notable progress, with the first-generation PF-06835919 completing Phase 2 trials for metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, and hereditary fructose intolerance, and the second-generation LY3522348 finishing Phase 1 evaluation in healthy participants, though key gaps including isoform selectivity and tissue-specific delivery remain unaddressed. Despite growing recognition of KHK's multifaceted roles in health and disease, existing literature lacks a consolidated synthesis of its regulation, tissue-specific functions, and translational progress. This review aims to provide a systematic overview of KHK's molecular characteristics, regulatory networks, pathophysiological roles, and therapeutic potential, establishing KHK as a promising actionable target for fructose-related disorders and offering a foundational framework to guide future research and drug development.