Iron metabolism: pathophysiology and pharmacology

Abstract

Iron is essential in many physiological processes, including DNA metabolism, oxygen transport, and cellular energy generation. Deregulated iron metabolism, which results in iron overload or iron deficiency, is observed in many different diseases. We here summarize recent progress in the pathophysiology and pharmacology of iron-overload diseases, such as hereditary hemochromatosis, as well as iron-deficiency disorders, which are typically associated with anemia. The role of iron in immunity and the connection between iron and cancer are also addressed. We finally summarize and discuss the current (pre-) clinical landscape of pharmacotherapies targeting key players involved in iron metabolism.

Keywords: anemia; cancer; hemochromatosis; inflammation; iron.

Figure 1. Key players in iron metabolism.

Iron is absorbed by enterocytes in the duodenum. Non-heme iron in ferric form is reduced by the duodenal cytochrome b (DCYTB) to ferrous iron, which can be transported into cells by divalent metal-ion transporter-1 (DMT1). Ferrous iron is released from enterocytes by ferroportin (Fpn) and oxidized by either membrane-bound hephaestin, ferroxidase or ceruloplasmin (Cp). In its ferric state, iron can be loaded onto transferrin, which allows for its transportation throughout the body to sites of high iron demand, such as the bone marrow, where the production of erythrocytes takes place. Senescent erythrocytes are recognized and phagocytosed by macrophages and degraded intracellularly. The iron obtained as part of this process is either secreted, stored inside ferritin, or employed as part of the labile iron pool. Hepcidin, the master regulator of iron metabolism, is produced and secreted by hepatocytes, where its production is regulated by iron stores and plasma iron levels. Hepcidin binds to Fpn and thereby initiates its internalization in and degradation by enterocytes, macrophages and hepatocytes, resulting in reduced plasma iron levels.

Figure 2. Therapeutic strategies targeting iron metabolism.

Deregulation of iron metabolism leads to hemochromatosis or iron deficiency. A) Primary hemochromatosis is often associated with low hepcidin expression resulting in high ferroportin (Fpn) occurrence and an increase in duodenal iron absorption. Therapeutic strategies include direct reduction of systemic iron by iron chelation or phlebotomy. B) Secondary hemochromatosis results from inefficient erythropoiesis leading to a possible undersupply with oxygen and an increased intestinal iron absorption leading to iron overload. Red blood cell transfusion or genetic engineering primarily targeting hemoglobin are employed to correct for the defective erythrocyte production. To reduce the occurring iron burden the hepcidin-Fpn axis or the intestinal iron absorption can be pharmacologically targeted. C) The increased demand of erythrocytes leads to iron deficiency which is accompanied by low systemic hepcidin levels, high Fpn expression, and increased duodenal iron absorption. Treatment includes direct elevation of iron levels via the administration of iron supplements or full blood. D) Anemia of chronic disease is provoked by an underlying inflammation reducing the circulating iron by hepcidin upregulation and Fpn downregulation. Therapeutically targeting hepcidin and Fpn or elevating the iron level by iron supplementation has been therapeutically exploited to ameliorate the anemic state.

Figure 3. Therapeutic strategies targeting iron metabolism in cancer.

Cancer is often accompanied by anemia of chronic disease mediated by hepcidin upregulation. This can be ameliorated by iron supplementation or hepcidin capture. Moreover, TfR and Fpn expression are altered, increasing the intracellular labile iron pool. Pharmacological strategies explored for cancer therapy include targeting iron transporters overexpressed on certain cancer cells, ferroptosis induction as well as iron depletion to inhibit proliferation.