ArticleSignal transduction and targeted therapy2026
Fructose 1-phosphate inhibits mannose phosphate isomerase to suppress hepatocellular carcinogenesis.
Article in Signal transduction and targeted therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.Cell death & disease · 2026Article
- Metabolic reprogramming is associated with symptomatic COVID-19: a serum proteomics and causal inference study identifying ALDOB and glycerol as candidate metabolic correlates.Frontiers in microbiology · 2026Article
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Abstract
Fructose consumption increases the risk of obesity-related metabolic diseases and some cancers, but its role in hepatocellular carcinogenesis (HCC) remains controversial. Animal studies suggest that high fructose promotes HCC, whereas human data fail to support the positive link between fructose intake and elevated risk of liver cancer. Moreover, fructose metabolism is progressively attenuated in HCC with the loss of key fructolytic enzymes, including fructose-1,6-bisphosphate aldolase B (ALDOB). Here, we report that fructose suppresses HCC through fructose 1-phosphate (F1P)-mediated inhibition of mannose phosphate isomerase (MPI) in the context of ALDOB deficiency. Transcriptomic and metabolic flux analyses using human HCC cells and tissues revealed that liver cancer cells retain a significant ability to metabolize fructose despite the downregulation of fructolytic genes, with ALDOB showing the earliest and most pronounced suppression compared with GLUT2 and KHK. Dietary supplementation with 10% fructose suppressed HCC in liver-specific Aldob knockout mice. Further spatial and single-cell transcriptomic analyses of clinical HCC samples revealed the spatiotemporal dynamics of fructolytic gene expression and identified subsets of cancer cells that retain fructose uptake and phosphorylation capacity (SLC2A2⁺/KHK⁺) but lack ALDOB expression. Upon fructose exposure, accumulated F1P binds to and inhibits MPI, reducing protein N-glycosylation and triggering apoptosis due to maladaptive ER stress. We further performed virtual high-throughput screening of FDA-approved and clinical-trial drugs and identified ebselen as a potent MPI inhibitor. Taken together, the results of our study reveal a novel mechanism by which dietary fructose inhibits HCC through the F1P-MPI axis, suggesting a therapeutic strategy targeting metabolic vulnerabilities in cancer.
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