Abstract 

The peptide hormone hepcidin is central to the regulation of iron metabolism, influencing the movement of iron into the circulation and determining total body iron stores. Its effect on a cellular level involves binding ferroportin, the main iron export protein, preventing iron egress and leading to iron sequestration within ferroportin-expressing cells. Hepcidin expression is enhanced by iron loading and inflammation and suppressed by erythropoietic stimulation. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis as occurs in anemia of chronic inflammation. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload such as hereditary hemochromatosis and iron loading anemias. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we assess the complex regulation of hepcidin, delineate the many binding partners involved in its regulation, and present an update on the development of hepcidin agonists and antagonists in various clinical scenarios.

2. Regulation of iron metabolism 

2.1 Systemic iron metabolism regulation

2.2 Cellular regulation of iron metabolism

(1) Duodenal enterocytes

(2) Reticuloendothelial macrophages

(3) Erythroblasts

3. Physiological regulation of hepcidin expression 

4. Hepcidin regulation by inflammation 

5. Hepcidin regulation by erythropoiesis 

6. Hepcidin regulation and hepcidin-independent regulation of iron absorption by hypoxia

7. Hepcidin-ferroportin axis regulates iron flows 

8. Hepcidin-ferroportin axis in disease 

8.1 Hereditary hemochromatosis 

8.2 Iron-loading anemias

8.3 Anemia of chronic inflammation 

8.4 Polycythemia vera

9. Targeting the hepcidin:ferroportin axis for therapeutic purposes

10. Conclusion

The discovery of hepcidin as a central regulator of iron metabolism and erythroid regulation of hepcidin by ERFE enabled a mechanistic exploration of aberrant iron metabolism in many hematopoietic and non-hematopoietic diseases. This enhanced understanding has within a relatively short timeframe lead to the development of novel compounds manipulating this pathway to support both exogenous agonist and antagonist function with multiple agents already undergoing clinical trials for several indications.