Review
The pathophysiology and pharmacology of hepcidin

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Highlights

  • The hormone hepcidin regulates systemic iron homeostasis.

  • Hepcidin deficiency or excess contributes to the pathogenesis of iron disorders.

  • Hepcidin agonists and antagonists are being developed as novel therapeutics.

Inappropriate production of the iron-regulatory hormone hepcidin contributes to the pathogenesis of common iron disorders. Absolute or relative deficiency of hepcidin causes iron overload in hereditary hemochromatosis and iron-loading anemias. Elevated hepcidin causes iron restriction in inflammatory conditions including autoimmune disease, critical illness, some cancers, and chronic kidney disease. Multiple agents targeting hepcidin and its regulators are under development as novel therapeutics for iron disorders. This review summarizes hepcidin biology and discusses the current landscape for hepcidin-targeting therapeutic strategies.

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.

References (74)

  • E. Nemeth

    Hepcidin is decreased in TFR2 hemochromatosis

    Blood

    (2005)
  • D.H. Lee

    Neogenin inhibits HJV secretion and regulates BMP induced hepcidin expression and iron homeostasis

    Blood

    (2010)
  • L. Silvestri

    The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin

    Cell Metab.

    (2008)
  • C.A. Enns

    Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage

    J. Biol. Chem.

    (2012)
  • M. Pak

    Suppression of hepcidin during anemia requires erythropoietic activity

    Blood

    (2006)
  • C. Besson-Fournier

    Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling

    Blood

    (2012)
  • A.E. Armitage

    Hepcidin regulation by innate immune and infectious stimuli

    Blood

    (2011)
  • A. Fernandes

    The molecular basis of hepcidin-resistant hereditary hemochromatosis

    Blood

    (2009)
  • R.L. Sham

    Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features

    Blood Cells Mol. Dis.

    (2005)
  • S.R. Pasricha

    Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with beta-thalassemia major: a longitudinal study

    Blood

    (2013)
  • J.B. Porter

    Optimizing iron chelation strategies in beta-thalassaemia major

    Blood Rev.

    (2009)
  • S.F. Libregts

    Chronic IFN-gamma production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis

    Blood

    (2011)
  • E. Ramos

    Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

    Blood

    (2012)
  • A. Nai

    Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia

    Blood

    (2012)
  • P.J. Schmidt

    An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe−/− mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia

    Blood

    (2013)
  • E. Corradini

    BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice

    Gastroenterology

    (2010)
  • M. Poli

    Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo

    Blood

    (2011)
  • I. Theurl

    Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats

    Blood

    (2011)
  • M. Nili

    Soluble repulsive guidance molecule c/hemojuvelin is a broad spectrum bone morphogenetic protein (BMP) antagonist and inhibits both BMP2- and BMP6-mediated signaling and gene expression

    J. Biol. Chem.

    (2010)
  • M. Schipperus

    CNTO328 (anti-IL-6 mAb) treatment is associated with an increase in hemoglobin (Hb) and decrease in hepcidin levels in renal cell carcinoma (RCC)

    Blood

    (2009)
  • J. Elliott

    Hyporesponsiveness to erythropoietin: causes and management

    Adv. Chronic Kidney Dis.

    (2009)
  • A. Akinc

    Targeting the hepcidin pathway with RNAi therapeutics for the treatment of anemia

    Blood

    (2011)
  • K.S. Cooke

    A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates

    Blood

    (2013)
  • T. Ganz et al.

    Hepcidin and disorders of iron metabolism

    Annu. Rev. Med.

    (2011)
  • E. Nemeth

    Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization

    Science

    (2004)
  • J.B. Goodnough

    Inhibition of hepcidin transcription by growth factors

    Hepatology

    (2012)
  • C. Latour

    Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin

    Hepatology

    (2014)
  • Cited by (0)

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