Proposed working model of iron-restricted erythropoiesis in apotransferrin-treated and TfR1 haploinsufficient β-thalassemic mice. Both TfR1 haploinsufficiency and exogenous apoTf result in decreased cellular iron in erythroid precursors, leading to decreased splenomegaly and ineffective erythropoiesis, which in turn causes decreased erythroferrone and hepdicin derepression. Increased hepcidin provides positive feedback to sustain iron-restricted erythropoiesis by preventing increased iron absorption and locking recycled iron within macrophages. ERFE, erythroferrone; Fe, iron; Fe-Tf, transferrin-bound iron; FPN1, ferroportin 1; thal, β-thalassemia.