Ketohexokinase deletion on liver and small intestine transcriptome

Dietary fructose is a major risk factor driving the progression of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the underlying fructose-induced nutrient-sensing pathway has remained unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK/PKM2/HIF-2α axis, driving MASH/HCC development. Fructose aberrantly stabilizes intestinal HIF-α compared to glucose; this effect is abrogated by a KHK inhibitor and genetic Khk deletion. Interestingly, reduced HIF-α stability in Khk deficient mice is rescued by a small-molecule inhibitor of pyruvate kinase M2 (PKM2). Conversely, Khk deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia, and markedly reduced blood neutrophil numbers. Moreover, Khk deficiency inhibits iron absorption in a HIF-2α-dependent manner. Finally, fructose promotes MASH/HCC progression in an iron-dependent manner. This study reveals a unique nutrient-sensing pathway by dietary fructose that is therapeutically targetable.