Summary
This mechanistic study demonstrates that dietary fructose drives MASH and HCC progression through a previously uncharacterised KHK/PKM2/HIF-2α nutrient-sensing pathway that abnormally enhances intestinal iron absorption. Using genetic knockout models and selective inhibitors, the authors show that KHK-dependent metabolic reprogramming stabilises intestinal HIF-α via PKM2-mediated glutamine oxidation, subsequently increasing plasma iron and disease burden. The findings identify a therapeutically targetable pathway linking high-fructose consumption to iron-dependent liver disease progression.
Regional applicability
This is a mechanistic laboratory study conducted in a model system, with no defined geographic setting. The findings regarding fructose and iron metabolism may be relevant to United Kingdom dietary and clinical contexts where high-fructose consumption and metabolic liver disease are prevalent, though in vivo validation in human populations and application to UK dietary guidelines would be required.
Key measures
Intestinal HIF-α stability, plasma iron levels, KHK enzyme activity, PKM2-mediated signalling, iron absorption rates, MASH and HCC progression markers, systemic iron status and anemia phenotypes
Outcomes reported
The study identified a fructose-induced nutrient-sensing pathway (KHK/PKM2/HIF-2α) that enhances intestinal iron absorption and drives metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC) progression. Mechanistic analysis revealed that fructose-induced metabolic reprogramming stabilises intestinal HIF-α, increasing plasma iron levels and promoting disease development in an iron-dependent manner.
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