Congratulations to Philip Gordts Lab for their recent publication
in Blood Advances
Halofuginone Suppresses Hepcidin by a Heparan Sulfate-dependent Mechanism to Treat Iron Disorders in Mice
Abstract Text:
Hepcidin, a liver-derived hormone, is the central regulator of systemic iron homeostasis. Elevated hepcidin levels contribute to iron-refractory iron deficiency anemia (IRIDA) and anemia of inflammation, both characterized by restricted iron availability. Current treatments, such as parenteral iron infusions, are often ineffective and pose risks of adverse reactions, underscoring the need for alternative therapeutic strategies targeting hepcidin. We previously identified a novel hepcidin regulatory pathway involving liver heparan sulfate (HS) proteoglycans (HSPGs), which modulate receptor-ligand interactions through their sulfated HS chains. Recently, we found that halofuginone impairs HS biosynthesis and considered whether it could be used as a hepcidin modulator. Here, we demonstrate that in human hepatoma (Hep3B) cells, halofuginone inhibits both basal and BMP6-induced hepcidin expression and p-SMAD1 signaling in a dose- and time-dependent manner. Consistently, Hep3B cells lacking HS (EXT1-/-) show no hepcidin suppression in response to halofuginone. In vivo administration of halofuginone reduces hepcidin expression in an iron-overload mouse model (8.3 g/kg carbonyl iron). This effect was absent in mice with impaired liver HS sulfation (Ndst1f/fAlbCre+), confirming that halofuginone suppresses hepcidin via HSPG-mediated mechanisms. Additionally, halofuginone decreased hepcidin expression in mice subjected to acute inflammation. These findings establish halofuginone as a potential therapeutic for mitigating hepcidin-driven iron restriction in anemic disorders.
Key Points
- Halofuginone downregulates hepcidin expression in hepatocytes by interfering with HSPG biosynthesis.
- Halofuginone lowers hepcidin in mouse models of iron-overload and inflammation, showing promise as a treatment for hepcidin-driven anemias