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Fructose metabolism and fructose kinase KHK-C/A are key factors in the development of lipid oversynthesis-promoted metabolic disorders and cancer. Here, we summarize and discuss the current knowledge about the specific features of fructose metabolism and the distinct roles of KHK-C and KHK-A in metabolic liver diseases and their relevant metabolic disorders and cancer, and we highlight the specific protein kinase activity of KHK-A in tumor development. In addition, different approaches that have been used to inhibit KHK and the exploration of KHK inhibitors in clinical treatment are introduced., Competing Interests: Conflict of interest All authors declare no conflict of interests., (Copyright © 2021 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.

Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop. Upregulated KHK-A promoted the phosphorylation and nuclear translocation of PKM2 in colorectal cancer. Nuclear PKM2 promoted EMT, aerobic glycolysis, CRLM and alternative splicing of KHK-A. [Display omitted] [ABSTRACT FROM AUTHOR]

Glomerular hypertrophy is a crucial factor of severe podocyte damage and proteinuria. Our previous study showed that high fructose induced podocyte injury. The current study aimed to explore a novel molecular mechanism underlying podocyte hypertrophy induced by high fructose. Here we demonstrated for the first time that high fructose significantly initiated the hypertrophy in rat glomeruli and differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of anti-inflammatory factor zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of microRNA-92a-3p (miR-92a-3p) and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing abnormal proliferation and apoptosis, were observed in vivo and in vitro. Moreover, high fructose increased ketohexokinase-A (KHK-A) expression in rat glomeruli and differentiated HPCs. Exogenous IL-6 stimulation up-regulated IL-6/STAT3 signaling and miR-92a-3p, reduced P57 expression and promoted podocyte proliferation, apoptosis and hypertrophy in vitro. The data from anti-inflammatory agent maslinic acid treatment or TTP siRNA transfection showed that high fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy. Whereas, KHK-A siRNA transfection remarkably restored high fructose-induced TTP down-regulation, IL-6/STAT3 signaling activation, podocyte overproliferation, apoptosis and hypertrophy in differentiated HPCs. Taken together, these results suggested that high fructose possibly increased KHK-A expression to down-regulate TTP, subsequently activated IL-6/STAT3 signaling to interfere with podocyte proliferation and apoptosis by up-regulating miR-92a-3p to suppress P57 expression, causing podocyte hypertrophy. Therefore, the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for high fructose diet-associated podocyte injury and proteinuria. • High fructose caused glomerular podocyte hypertrophy. • IL-6/STAT3 signaling was activated in high fructose-induced podocyte hypertrophy. • High fructose decreased TTP to activate IL-6/STAT3 signaling by increasing KHK-A. [ABSTRACT FROM AUTHOR]