Hepcidin: A Promising Therapeutic Target for Iron Disorders: A Systematic Review

Abstract

Iron is required for most forms of organisms, and it is the most essential element for the functions of many iron-containing proteins involved in oxygen transport, cellular respiration, DNA replication, and so on. Disorders of iron metabolism are associated with diverse diseases, including anemias (e.g., iron-deficiency anemia and anemia of chronic diseases) and iron overload diseases, such as hereditary hemochromatosis and β-thalassemia. Hepcidin (encoded by Hamp gene) is a peptide hormone synthesized by hepatocytes, and it plays an important role in regulating the systematic iron homeostasis. As the systemic iron regulator, hepcidin, not only controls dietary iron absorption and iron egress out of iron storage cells, but also induces iron redistribution in various organs. Deregulated hepcidin is often seen in a variety of iron-related diseases including anemias and iron overload disorders. In the case of iron overload disorders (e.g., hereditary hemochromatosis and β-thalassemia), hepatic hepcidin concentration is significantly reduced.Since hepcidin deregulation is responsible for iron disorder-associated diseases, the purpose of this review is to summarize the recent findings on therapeutics targeting hepcidin.Continuous efforts have been made to search for hepcidin mimics and chemical compounds that could be used to increase hepcidin level. Here, a literature search was conducted in PubMed, and research papers relevant to hepcidin regulation or hepcidin-centered therapeutic work were reviewed. On the basis of literature search, we recapitulated recent findings on therapeutic studies targeting hepcidin, including agonists and antagonists to modulate hepcidin expression or its downstream signaling. We also discussed the molecular mechanisms by which hepcidin level and iron metabolism are modulated.Elevating hepcidin concentration is an optimal strategy to ameliorate iron overload diseases, and also to relieve β-thalassemia phenotypes by improving ineffective erythropoiesis. Relative to the current conventional therapies, such as phlebotomy and blood transfusion, therapeutics targeting hepcidin would open a new avenue for treatment of iron-related diseases.

FIGURE 1

Hepcidin modulates the systemic iron levels. Hepcidin–FPN axis is the key regulator of systemic iron. FPN, the only known iron exporter, is fine-tuned by hepcidin. Hepcidin is synthesized by hepatocytes that promote the degradation of FPN. The regulation of hepcidin is via three causes. (1), Blocking iron release from macrophages. Spleen is the main iron-recycling organ where aged red blood cells are engulfed by macrophages. Fpn1 deficiency induces iron accumulation in spleen. (2), Reducing iron release from hepatocytes. Liver is the main iron storage organ, and FPN degradation would decrease iron transfer to plasma, leading to iron overload. (3), Inhibiting iron absorption by enterocytes. Enterocyte is the main dietary iron uptake site. The degradation of FPN in enterocytes prevents the iron compensation for its loss, including shedding of epithelial cells, hair, sweat, and menstrual blood. FPN = ferroportin.

FIGURE 2

The mechanisms responsible for Hamp transcription. Hamp transcription is regulated by diverse signaling pathways, including iron concentration, inflammation, erythropoiesis, and sex hormone. (1), Iron levels contribute to Hamp transcription through the Smad signaling. In an iron-replete condition, iron binds to TfR2, and then forms a complex with HFE, HJV, and BMPRs to promote Smad1/5/8 activation. In contrast, iron binds to TfR1 and fails to stimulate Hamp transcription in iron deficiency. (2), BMPs are involved in hepcidin regulation. BMPs bind to BMPRs, and thus form BMPs, BMPRs, and HJV complex to activate Smad phosphorylation and promote Hamp transcription. (3), The preinflammatory factors (including IL-6, IL-22, and IL-1β) and activin B incur Hamp up-regulation. IL-6 and IL-22 can bind to its receptor to increase hepcidin expression via Stat3, but IL-1β and activin B (a member of the TGF-β protein superfamily) increase Hamp transcription through the BMP-Smad signaling. (4), Cytokine factors produced by erythroblasts are also implicated in hepcidin regulation. GDF15, TWSG1, and ERFE are recognized to be the hepcidin regulators. GDF15 could modulate hepcidin expression through BMP inhibition, whereas the detailed mechanisms underlying the action of TWSG1 and ERFE in Hamp repression remain unclear. (5) Endogenous hormones (such as estrogen) negatively regulate Hamp transcription by binding to the ERE of Hamp promoter. BMP = bone morphogenetic protein, BMPR = bone morphogenetic protein receptor, ERFE = erythroferrone, GDF = growth differentiation factor, HFE = hemochromatosis protein, HJV = hemojuvelin, IL = interleukin.

FIGURE 3

The mechanism underlying mini-hepcidin action. Mini-hepcidin is a synthesized polypeptide, analogs to natural hepcidin. It exhibits a high binding affinity to FPN, which could facilitate the latter's internalization and degradation, and thus diminish iron egress from macrophages and hepatocytes and iron uptake through enterocytes. FPN = ferroportin.

FIGURE 4

The mechanism of antisense oligonucleotide for hepcidin induction. TMPRSS6 is a transmembrane protease serine 6, and it cleavages HJV to inactivate the Smad signaling. Antisense oligonucleotide molecules could silence the mRNA of Tmprss6, and then down-regulate the expression of Tmprss6 that functions to increases the stability of HJV. HJV is a part of the complex formed by BMPRs to induce Hamp transcription. BMPR = bone morphogenetic protein receptor, HJV = hemojuvelin.

FIGURE 5

The mechanism by which sHJV.Fc conducts hepcidin suppression. sHJV.Fc is a soluble HJV–Fc fusion protein which can bind to BMPs to prevent the latter's interaction with HJV. HJV is a core composition within the BMP-Smad signaling. The association of sHJV.Fc with BMPs decreases the phosphorylation of Smad1/5/8 and thus reduces Hamp transcription. BMP = bone morphogenetic protein, HJV = hemojuvelin.

FIGURE 6

The mechanism of IL-6 Ab in hepcidin suppression. IL-6-provoked proinflammation effects activate Hamp expression through the Stat3 signaling. Blocking IL-6-activated Stat3 signaling would be an optimal strategy to reduce hepcidin level under inflammation. Tocilizumab is a humanized anti-IL-6R antibody, and it works to inactivate the phosphorylation of Stat3. IL = interleukin.