Molecular pathophysiology of iron homeostasis during anemia and targeted intervention – MARINADE

Anemia, defined as a decreased quantity of circulating red blood cells, is a major source of morbidity and mortality affecting a-third of the worldwide population. As a functional component of erythrocytes hemoglobin, iron is essential for oxygen storage and transport. The liver-derived peptide hepcidin is the master regulator of iron homeostasis. During anemia, the erythroid hormone erythroferrone regulates hepcidin synthesis to ensure the proper supply of iron to the bone marrow for red blood cells synthesis. However, we provided evidence that another factor may exert a similar function. We identified a previously undescribed suppressor of hepcidin that is highly induced in the liver in response to hypoxia during the recovery from anemia and in thalassemic mice. We demonstrated that this hepatokine is a potent suppressor of hepcidin in vitro and in vivo. Our preliminary data further indicated that it acts by impairing the canonical BMP-SMAD signaling cascade that governs hepcidin regulation but the molecular mechanism is unknown. Our aims are to confirm the role this hepatokine in hepcidin regulation and iron metabolism, to identify its exact mechanism, to explore its involvement in human pathologies and to investigate the therapeutic potential of its manipulation in murine models of anemia. Successful completion of this project will open new areas of investigation and provide a better understanding of the pathophysiology of anemia and hypoxia and liver physiology. Ultimately, it will lead to the development of new therapeutic strategies for the treatment of various forms of anemias for which current treatments remain largely ineffective.