Fructose is a major component of dietary sugar and its overconsumption 
exacerbates key pathological features of metabolic syndrome. The central 
fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two 
isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative 
splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose 
compared with KHK-A and is produced primarily in the liver, thus restricting 
fructose metabolism almost exclusively to this organ. Here we show that 
myocardial hypoxia actuates fructose metabolism in human and mouse models of 
pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) 
activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. 
Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A 
alone, in mice, suppresses pathological stress-induced fructose metabolism, 
growth and contractile dysfunction, thus defining signalling components and 
molecular underpinnings of a fructose metabolism regulatory system crucial for 
pathological growth.