Study Links Dietary Fructose to Liver Disease Progression Through Iron Absorption Pathway
A new preprint study identifies a molecular pathway by which dietary fructose drives progression of metabolic liver disease (MASH) and hepatocellular carcinoma (HCC) by enhancing iron absorption in the intestine. The mechanism involves a signaling cascade — KHK/PKM2/HIF-2α — that stabilizes a protein promoting iron uptake, raising plasma iron levels and fueling liver damage. The findings suggest several points along this pathway may be therapeutically targetable, potentially offering new treatment strategies for fructose-driven liver disease.
Researchers report that dietary fructose abnormally stabilizes the intestinal protein HIF-2α through a chain of metabolic events involving the enzymes ketohexokinase (KHK) and pyruvate kinase M2 (PKM2), ultimately increasing iron absorption from the gut. Elevated plasma iron levels resulting from this process appear to drive the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). The study found that genetically deleting KHK in mice not only blocked HIF-2α stabilization but also caused spontaneous systemic iron deficiency and hypochromic anemia, underscoring the pathway's central role in iron homeostasis. A selective PKM2 inhibitor was able to restore normal HIF-2α stability in KHK-deficient mice, confirming PKM2 as a key intermediary. The fructose-induced metabolic reprogramming was found to shift cells toward glutamine-dependent oxidative phosphorylation, which is the proximate trigger for HIF-2α stabilization. These results establish iron as a critical mediator linking high fructose consumption to liver disease progression, and identify KHK, PKM2, and HIF-2α as candidate drug targets. The work was posted as a preprint on bioRxiv and has not yet undergone formal peer review.
What's missing
As a preprint, this study has not yet been peer-reviewed. Key open questions include whether findings in mouse models translate to humans, what dietary fructose thresholds are relevant to human disease, and how this pathway interacts with other known drivers of MASH such as obesity and insulin resistance. The study does not address long-term safety of inhibiting KHK or PKM2 pharmacologically.
What different sources said
- bioRxivCenter
Dietary fructose promotes MASH/HCC progression through enhanced intestinal HIF-2α-dependent iron absorption
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