By William Aird

  • Iron is an essential micronutrient required for many cellular and organismal processes in nearly all living organisms.
  • Absorption, storage, and transport of iron atoms are tightly regulated.
  • Increased erythropoiesis generates a large iron demand:12
    • It has long been understood that the ability to rapidly mobilize and absorb additional iron in response to increased erythropoietic activity would hasten recovery in response to hematopoietic stress, such as blood loss or hypoxia.
    • Expression of hepcidin by the liver was found to decrease in response to anemia and this suppression was shown to be dependent on the presence of functional erythroid precursors.
    • Initially factors such as growth differentiation factor 15 (GDF15) and twisted gastrulation BMP signaling modulator 1 (TWSG1) were identified as possible candidates for this erythroid regulator of hepcidin.
    • Later studies led to the identification of erythroferrone as the primary mediator or erythropoiesis-mediated suppression of hepcidin.
  • Hepcidin:
    • Master regulator of systemic iron homeostasis.
    • A small peptide hormone produced by the liver (hepcidin gene HAMP).
    • Circulates at nanomolar concentrations.
    • Controls iron transit into plasma by internalizing the sole cellular iron exporter, ferroportin:
      • Preventing:
        • Recycled iron in macrophages from reaching the plasma.
        • Dietary iron absorbed in the intestine from reaching the plasma.
      • Thus reducing iron availability.
    • Hepcidin expression is:
      • Increased by:
        • Iron loading in the liver via the canonical BMP-SMAD signaling pathway.
        • Inflammation via IL-6-driven JAK-STAT signaling.
      • Decreased by:
        • Iron deficiency via matriptase-2 (encoded by TMPRSS6)-mediated downregulation of hemojuvelin, a coreceptor for BMP signaling.
        • Increased erythropoiesis via erythropoietin (EPO)-induced expression of erythroferrone by erythroblasts in the bone marrow or spleen.
  • Erythroferrone:
    • Discovered in 2014 as a signal that communicates the iron demand of erythroid cells liver in the bone marrow to the liver and other organs to regulate the iron supply.3
    • Belongs to the C1Q tumor necrosis factor-related protein family.4
    • Produced by erythroblasts in response to EPO via a STAT5-dependent pathway characterized by:5
      • An N-terminal extended region containing a variably long collagen-like multimerization motif.
      • A C-terminal globular head that structurally resembles that of TNF-α or the C1q complement protein.
    • Represents a response to stress erythropoiesis; produced by developing erythroid cells in response to:
      • Hemorrhage
      • Hypoxia
      • Hemolysis
      • Other erythropoietic stimuli
    • Suppresses hepcidin transcription in the liver by inhibiting hepatic BMP–SMAD signaling,6 resulting in:
      • Decreased circulating levels of hepcidin.
      • Increased iron absorption from the diet.
      • Increased mobilization of iron stores in hepatocytes and macrophages.
      • Increased iron availability for erythropoiesis during periods of high erythropoietic demand.7
    • Physiological role in erythropoietic recovery
    • Pathological role in anemias with ineffective erythropoiesis:
      • High EPO levels lead to excessive production of erythroferrone with:
        • Expanded population of erythroblasts
        • Development of iron overload 
    • In summary, erythroferrone is an erythroid hormonal suppressor of hepcidin produced by EPO-stimulated erythroblasts.8
  • Mouse models:
    • In response to EPO, either endogenously produced after phlebotomy or administered by injection, erythroblasts at all stages of differentiation increased their expression of Erfe. This process was dependent on the activity of the STAT5 transcription factor. 9
    • Erythroferrone-deficient mice fail to suppress hepcidin rapidly after hemorrhage and exhibit a delay in recovery from blood loss.10
    • Overexpression of erythroferrone results in dose-dependent:
      • Relative hepcidin deficiency
      • Iron overload
  • Dysregulation of EPO-erythroferrone-hepcidin pathway in Ineffective erythropoiesis:
    • Plasma ERFE erythroferrone are greatly increased in anemias with ineffective erythropoiesis.11
    • Thalassemia:
      • Anemia in β-thalassemia intermedia and major is associated with:
        • Decreased hepcidin expression
        • Excessive iron absorption
        • Systemic iron overload
      • In human patients with non-transfusion-dependent thalassemia, serum erythroferrone levels are increased compared with that in healthy controls and correlate inversely with serum hepcidin concentrations.[/efn_note]34396049[/efn_note]
      • Transfusion in patients with thalassemia:12
        • Reduced serum EPO levels
        • Increases hepcidin production
        • Decreased serum erythroferrone levels
    • PK deficiency:
      • Patient with PK deficiency have been show to have:13
        • Significantly increased serum EPO levels
        • Decreased serum hepcidin levels
        • Increased serum erythroferrone compared to controls
    • Similar findings in other hereditary hemolytic anemias including:14
      • Hereditary xerocytosis
      • Sickle cell disease
      • Hereditary spherocytosis
  • Open questions:
    • Could erythroferrone inhibition be used therapeutically to reduce iron overload in states of ineffective erythropoiesis?
    • Does erythroferrone have other functions beyond its role in iron homeostasis?
    • Are there other endogenous sources of erythroferrone?
    • Are there other erythroid regulators of hepcidin?


1. Erythroferrone structure, function, and physiology: Iron homeostasis and beyond. J Cell Physiol. 2021 Jul;236(7):4888-4901.

2. Erythroferrone in iron regulation and beyond. Blood. 2022 Jan 20;139(3):319-321.

3. Erythroferrone: An Erythroid Regulator of Hepcidin and Iron Metabolism. Hemasphere. 2018 Mar 28;2(2):e35.