Ketohexokinase deletion on liver and small intestine transcriptome

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.