Fructose slows liver tumors in mice when key sugar-processing gene is missing, may lead to new treatments

The context for this research is that the relationship between fructose and liver cancer has long been controversial: animal studies generally suggest that high fructose intake promotes hepatocellular carcinoma (HCC), whereas human data do not support a positive association; at the same time, fructose metabolism progressively weakens as HCC advances, with downregulation of fructose-1,6-bisphosphate aldolase B (ALDOB) occurring earlier and more markedly than for GLUT2 and KHK^[1]. The key question is therefore not simply whether fructose is beneficial, but whether the same nutrient may have different effects after the tumor's metabolic state changes.

Researchers from City University of Hong Kong gave some liver-specific Aldob knockout mice drinking water supplemented with 10% fructose. Fructose significantly suppressed tumor formation and growth in mice lacking ALDOB, while it had almost no effect in mice with normal gene expression. Mechanistically, F1P accumulated in cancer cells and directly bound mannose phosphate isomerase (MPI), inhibiting its activity, weakening protein N-glycosylation, triggering endoplasmic reticulum stress and inducing apoptosis; molecular docking and dynamics simulations identified Arg295 on MPI as the binding site. Supplementing mannose bypassed the blocked step and reversed fructose's anticancer effect. From approximately 2,000 drugs approved by the U.S. Food and Drug Administration or in clinical trials, the team selected ebselen. In mouse models, the drug suppressed liver cancer growth and produced a synergistic effect with sorafenib. The team filed a patent application for using ebselen to treat liver cancer (needs verification).

The concurrent paper supports the conclusion that the effect depends on the ALDOB-deficient metabolic context: F1P inhibits MPI, reduces protein N-glycosylation, and triggers apoptosis through maladaptive endoplasmic reticulum stress; spatial and single-cell transcriptomic analyses also identified SLC2A2⁺/KHK⁺ cancer-cell subsets in clinical HCC samples that retained fructose uptake and phosphorylation capacity but lacked ALDOB expression^[1]. This advances the work from a dietary intervention to an F1P-MPI mechanism and a druggable target. However, the reported screening scale of approximately 2,000 candidate drugs was traced only to industry-media coverage rather than the primary verification material, so it should be treated as media-exclusive and cannot support conclusions about candidate coverage or hit probability (needs verification)。

The material does not disclose when a human trial of ebselen for liver cancer will begin, its phase, patient population, dosing regimen, or efficacy and safety results, nor does it provide human evidence for combination with sorafenib or specify the patent application's terms. The next steps include optimizing preclinical dosing, designing human studies and preparing regulatory submissions; whether dietary fructose can become a treatment for liver cancer patients and its applicability across tumor metabolic states remain to be confirmed (needs verification).