Modulation of the E3-ubiquitin ligase RNF217 alters ferroportin levels in enterocytes and iron loading in murine hemochromatosis

Abstract

Abstract Excess iron induces tissue toxicity in various conditions, including hereditary hemochromatosis (HH). Hepcidin, a liver-derived hormone encoded by the HAMP gene, plays a pivotal role in regulating systemic iron by mediating the degradation of ferroportin (FPN), the sole cellular iron exporter. Previous research found that the E3 ubiquitin ligase RNF217 is a key regulator of iron homeostasis by directly affecting FPN degradation; however, the role of RNF217 overexpression in iron-overload disorders such as HH is poorly understood. To address this question, we generated both global and intestine-specific Rnf217-overexpressing mice and then crossed these mice with hemojuvelin knockout (Hjv−/−) mice, a model for studying hemochromatosis. We found that both global and intestine-specific Rnf217 overexpression caused an identical rescue of the HH phenotype, implicating duodenal enterocytes as the main site where RNF217 overexpression exerts its beneficial effects. Moreover, we found that intestinal Rnf217 overexpression significantly reduced iron accumulation in the serum and in vital organs; importantly, these effects were not correlated with hepcidin levels. In summary, our findings demonstrate that intestinal RNF217 overexpression can directly suppress iron absorption by modulating FPN protein levels, bypassing hepcidin. This suggests a possible therapeutic strategy for iron-overload disorders, warranting further study to establish its clinical potential.