Figure 1. Model for the Tf/TfR1 cycle and overview of receptor-mediated pathways for endocytosis of extracellular heme and Hb.

Holo-Tf binds TfR1 on the cell surface; the complex internalizes in endosomes, where acidification promotes iron release from Tf. Fe³⁺ is reduced to Fe²⁺ by Steap3, and then transported out of endosomes into the cytosol through DMT1 and Zip14. Both Tf and TfR1 return to the cell surface, where at neutral pH iron-depleted Tf is released from TfR1 and TfR1 is ready to bind more iron-laden Tf for another round of endocytosis. CD163 is a receptor for uptake of extracellular Hb bound to Hp. LRP/CD91 represents the pathway for uptake of heme–Hx complexes. Entocytosed heme can be further metabolized into bilirubin, Fe and carbon monoxide.