lterations in cellular metabolism may contribute to tumor proliferation and survival. Upregulation of the facilitative glucose transporter (GLUT) plays a key role in promoting cancer. GLUT5 mediates modulation of fructose utilization

and its overexpression has been associated with poor prognosis in several cancers. However

its metabolic regulation remains poorly understood. Here

we demonstrated elevated GLUT5 expression in human cholangiocarcinoma (CCA)

using RNA sequencing data from samples of human tissues and cell lines

as compared to normal liver tissues or a cholangiocyte cell line. Cells exhibiting high-expression of GLUT5 showed increased rates of cell proliferation and ATP production

particularly in a fructose-supplemented medium. In contrast

GLUT5 silencing attenuated cell proliferation

ATP production

cell migration/invasion

and improved epithelial–mesenchymal transition (EMT) balance. Correspondingly

fructose consumption increased tumor growth in a nude mouse xenograft model

and GLUT5 silencing suppressed growth

supporting the tumor-inhibitory effect of GLUT5 downregulation. Furthermore

in the metabolic pathways of fructolysis-Warburg effect

the expression levels of relative downstream genes

including ketohexokinase (KHK)

aldolase B (ALDOB)

lactate dehydrogenase A (LDHA)

and monocarboxylate transporter 4 (MCT4)

as well as hypoxia-inducible factor 1 alpha (HIF1A)

were altered in a GLUT5 expression-dependent manner. Taken together

these findings indicate that GLUT5 could be a potential target for CCA therapeutic approach via metabolic regulation.