Genetics and cell biology

Regulation of iron metabolism

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Group leader

Antonella Nai

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The Unit is interested in dissecting the complex mechanism/s that control systemic iron regulation in physiologic and pathologic conditions. The latter include genetic forms of Hereditary Hemochromatosis and ineffective erythropoiesis as Thalassemias, acquired forms of anemia, and metabolic disorders (as metabolic dysfunction-associated fatty liver disease, MASLD).

Over the years the unit has contributed to unravel the role of different players in the control of the hepcidin/ferroportin axis, the main regulator of iron absorption and recycling, and in the crosstalk between the liver, the main regulator of iron/hepcidin, and erythroid cells, the main consumers of iron.

More in detail, we have defined the erythroid role of the second transferrin receptor (TFR2) as a brake of erythropoietin (EPO) signaling, proving that hematopoietic Tfr2 deletion causes erythrocytosis and ameliorates anemia of inherited and acquired etiology.

Moreover, the team has recently identified a new level of hepcidin control mediated by the immunophilin FKBP12, which binds to and inhibits the BMP receptor ALK2, thus negatively regulating hepcidin transcription. FKBP12 targeting in vivo could be a promising therapeutic approach to several hepcidin-related diseases, as Hemochromatosis and Thalassemia.

Research activity

The lab is currently addressing different lines of investigation. In detail:

1. We are investigating the molecular mechanism of TFR2-mediated hepcidin upregulation in hepatocytes and the role of TFR2 as a modulator of EPO receptor processing, function and signaling in erythroid cells.

 2. Capitalizing on the new knowledge of the role of TFR2 as a brake of erythropoiesis, we are exploring TFR2 as a therapeutic target for congenital and acquired anemias to identify novel strategies to boost the erythroid response.

3. We are investigating the role of new players identified by the Unit in the regulation of the BMP-SMAD pathway and hepcidin expression and their pharmacological modulation as a new potential therapeutic approach for diseases characterized by hepcidin insufficiency.

4. We are deciphering the link between iron and lipid metabolism and trying to unravel the role of BMP-SMAD signaling and hepcidin regulation in the liver in MASLD and its complication steatohepatitis (MASH).

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