Fructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream, and its fasting blood levels are much lower (~0.005 mM) than glucose (~5.5 mM) under normal physiological conditions. Therefore, it remains unclear where fructose is derived from and how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the polyol pathway is active in cancer cells and is capable of converting up to 50% of glucose into fructose, resulting in enhanced glycolysis and ATP production. Inhibition of the polyol pathway severely decreased fructose production in cancer cells and suppressed their glycolysis, ATP production, and growth rate. Furthermore, we determined that the glucose transporter, SLC2A8/GLUT8, was a crucial transporter to export intracellular fructose outside cells. Taken together, our study identified an overlooked but critically essential fructose-producing pathway in cancer cells as an integral part of their metabolic reprogramming leading to enhanced glycolysis, cell proliferation, and malignancy. ### Competing Interest Statement The authors have declared no competing interest.
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