Fructose Metabolism in Cancer Pathophysiology

Fructose, a monosaccharide abundant in diet and generated endogenously via the polyol pathway, has emerged as a key substrate in cancer cell metabolism. Tumours frequently upregulate specific transporters, notably GLUT5 (SLC2A5), to import fructose when glucose is limiting. Once internalised, fructose is rapidly phosphorylated by ketohexokinase (KHK) into fructose-1-phosphate and channelled into glycolysis and lipogenesis. This metabolic reprogramming can amplify ATP production, nucleotide synthesis and fatty acid accumulation, while also generating byproducts such as lactate and uric acid that promote the Warburg effect, redox imbalance and inflammatory signalling. Moreover, fructose metabolism intersects with major regulatory pathways: activation of mTORC1, suppression of AMPK and induction of stress-responsive transcription factors drive cell proliferation, survival and motility. Recent evidence identifies alternative roles for key enzymes; for example, nuclear KHK-A functions as a protein kinase to modulate epithelial-mesenchymal transition, and ATF4-dependent induction of fructolytic proteins under glucose deprivation supports tumour growth in hostile microenvironments. Collectively, these insights underscore fructose as a versatile fuel that contributes to tumour progression, metastasis and angiogenesis, and highlight components of fructose metabolism as potential therapeutic targets to disrupt cancer-specific bioenergetic and signalling circuits.

Research from Nature Portfolio

Recent studies have elucidated non-canonical functions of ketohexokinase in metastatic progression. One investigation demonstrated that, upon fructose stimulation, the KHK-A isoform translocates to the nucleus of breast cancer cells. There, it phosphorylates the adaptor protein YWHAH, thereby recruiting transcriptional repressors to the CDH1 promoter and facilitating epithelial-mesenchymal transition and cell invasion. This finding reveals a direct link between dietary sugar and gene regulation underlying metastasis.

Another study has focused on glioblastoma multiforme, where glucose scarcity triggers a metabolic switch to fructolysis. Glucose deprivation induces activating transcription factor 4 (ATF4), which upregulates both GLUT5 and aldolase B (ALDOB), enabling efficient fructose consumption. Disruption of this ATF4-dependent programme inhibits colony formation in vitro and reduces tumour burden in vivo, establishing fructolysis as a hallmark of aggressive brain tumours and a promising therapeutic target.

Fructose Metabolism in Cancer Pathophysiology publication trend

The graph below shows the total number of articles in fructose metabolism in cancer pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Fructolysis: The metabolic pathway that degrades fructose to glycolytic intermediates and lipogenic precursors.

Polyol pathway: A two-step process converting glucose to sorbitol via aldose reductase, then to fructose via sorbitol dehydrogenase.

Ketohexokinase (KHK): The enzyme that phosphorylates fructose to fructose-1-phosphate, with tissue-specific isoforms A and C.

GLUT5 (SLC2A5): A facilitative transporter specialised for cellular uptake of fructose.

ATF4: Activating transcription factor 4, a stress-responsive regulator that controls expression of metabolic and adaptive genes under nutrient limitation.

ALDOB: Aldolase B, the enzyme that cleaves fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde in fructolysis.

Warburg effect: The tendency of cancer cells to favour aerobic glycolysis over oxidative phosphorylation, even in the presence of oxygen.

References

1. AKR1B1-dependent fructose metabolism enhances malignancy of cancer cells. Cell Death & Differentiation (2024).
2. Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells. Journal of Experimental & Clinical Cancer Research (2023).
3. Fructose contributes to the Warburg effect for cancer growth. Cancer & Metabolism (2020).
4. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. JCI Insight (2020).
5. Ketohexokinase-A acts as a nuclear protein kinase that mediates fructose-induced metastasis in breast cancer. Nature Communications (2020).
6. ATF4-dependent fructolysis fuels growth of glioblastoma multiforme. Nature Communications (2022).