Fig. 2.

Iron metabolism in hepatocytes. A–F: TfR-dependent route (the Tf cycle). A: Two ferric irons (Fe³⁺) in the plasma bind to Tf with high affinity. B: Fe₂-Tf binds to TfR1 on the surface of hepatocytes. C: Fe₂-Tf/TfR1 complex is taken up into hepatocytes by endocytosis. D: The pH of endosomes is lowered to 5–6 by an action of proton pumps, and then Fe³⁺ is released at this acidic pH. E: Released Fe³⁺ becomes ferrous iron (Fe²⁺) by the enzymes of STEAP family, and then Fe²⁺ moves across the endsomal membrane through the DMT1 transporter. F: Apo-Tf still binds to TfR1 at the lower pH of endosomes. Apo-Tf/TfR1 is returned to the surface of the hepatocyte for further iron binding and uptake. G: TfR-independent route. At the high level of iron in plasma, NTBI is reduced to Fe²⁺ by ferric reductase. Fe²⁺ is rapidly transported into the hepatocytes through DMT1.