Trends in Pharmacological Sciences
ReviewThe pathophysiology and pharmacology of hepcidin
Section snippets
Hepcidin regulates systemic iron homeostasis
The peptide hormone hepcidin is primarily produced in hepatocytes and it regulates plasma iron concentrations [1]. The molecular target of hepcidin is the cellular iron exporter ferroportin [2]. Ferroportin supplies iron into plasma from duodenal enterocytes engaged in dietary iron absorption, from macrophages of the spleen and liver that recycle old red blood cells, and from hepatocytes involved in iron storage (Figure 1) [3]. Hepcidin is the ligand for ferroportin and their interaction
Hepcidin deficiency in iron overload disorders
Hepcidin deficiency is the pathogenic cause of iron overload in most forms of hereditary hemochromatosis. Hepcidin insufficiency results from deleterious mutations in the genes encoding hepcidin regulators (HFE, TfR2, and HJV) or hepcidin itself [1]. In all of these cases, dietary iron is hyperabsorbed, resulting in deposition of excess iron in the liver and other parenchyma. The degree of hepcidin deficiency correlates with the severity of iron overload: mutations in HJV or hepcidin, which are
Manipulation of the hepcidin pathway for therapeutic purposes
Because hepcidin deficiency or excess plays important roles in the pathogenesis of various iron disorders, hepcidin agonists and antagonists may be potentially useful in clinical practice. Genetic studies in animal models have provided initial proof of the principle that hepcidin could be an effective therapeutic target. For example, overexpression of hepcidin in Hfe−/− mice, a model of the most common form of human hereditary hemochromatosis, prevented the liver iron overload normally seen in
Hepcidin antagonists
Elevated hepcidin concentrations are associated with various pathologies: anemia of inflammation, chronic kidney disease, some cancers, and iron-refractory iron deficiency anemia. These conditions are usually treated with erythropoiesis-stimulating agents (ESAs) with or without high-dose intravenous iron. However, the effectiveness of these therapies is thought to be impaired by high hepcidin. Hepcidin-mediated iron restriction likely contributes to erythropoietin resistance, and high hepcidin
Concluding remarks
The hepcidin–ferroportin axis plays an important role in the pathogenesis of iron disorders including iron overload diseases and iron-restricted anemias. It is therefore not surprising that within only a dozen years since the first publications on hepcidin, multiple hepcidin-targeting strategies have been developed. Although most agents have only been evaluated in preclinical studies, several have reached human clinical trials. It is still too early to try to assess which of the many approaches
Disclaimer statement
Elizabeta Nemeth is a stockholder and consultant for Intrinsic LifeSciences, a biotech company developing hepcidin diagnostics, and Merganser Biotech, a biotech company developing hepcidin therapeutics. Piotr Ruchala is a stockholder and consultant for Merganser Biotech.
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