Dietary fructose promotes MASH/HCC progression through enhanced intestinal HIF-2α-dependent iron absorption

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 remains unclear. Here, we report that fructose facilitates iron absorption through the (Ketohexokinase) KHK/PKM2/HIF-2α axis, driving MASH and HCC development. Fructose aberrantly stabilizes intestinal HIF-α; this effect is abrogated by a KHK inhibitor and genetic Khk deletion. Mechanistically, fructose-induced metabolic reprogramming drives glutamine-dependent oxidative phosphorylation, leading to HIF-α stabilization, which is mediated by pyruvate kinase M2 (PKM2). A selective PKM2 inhibitor rescues reduced intestinal HIF-α stability in Khk -deficient mice. Furthermore, dietary fructose increases plasma iron levels. Conversely, Khk -deficient mice exhibit spontaneous systemic iron deficiency, characterized by hypochromic anemia. Moreover, Khk deficiency inhibits iron absorption in a HIF-2α-dependent manner. Finally, fructose promotes MASH and HCC progression in an iron-dependent manner. This study reveals a unique, therapeutically targetable nutrient-sensing pathway utilized by dietary fructose.