Dietary fructose is primarily metabolized in the liver. Here we demonstrate 
that, compared with normal hepatocytes, hepatocellular carcinoma (HCC) cells 
markedly reduce the rate of fructose metabolism and the level of reactive oxygen 
species, as a result of a c-Myc-dependent and heterogeneous nuclear 
ribonucleoprotein (hnRNP) H1- and H2-mediated switch from expression of the 
high-activity fructokinase (KHK)-C to the low-activity KHK-A isoform. 
Importantly, KHK-A acts as a protein kinase, phosphorylating and activating 
phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote pentose phosphate 
pathway-dependent de novo nucleic acid synthesis and HCC formation. Furthermore, 
c-Myc, hnRNPH1/2 and KHK-A expression levels and PRPS1 Thr225 phosphorylation 
levels correlate with each other in HCC specimens and are associated with poor 
prognosis for HCC. These findings reveal a pivotal mechanism underlying the 
distinct fructose metabolism between HCC cells and normal hepatocytes and 
highlight the instrumental role of KHK-A protein kinase activity in promoting de 
novo nucleic acid synthesis and HCC development.