Transferrin (Tf) is an approximately 80-kDa plasma glycoprotein synthesized and secreted predominantly by hepatocytes. It migrates mainly within the β1-globulin fraction on serum protein electrophoresis and serves as the principal physiological iron-transport protein in the human circulation. Transferrin consists of two structurally homologous lobes, termed the N- and C-lobes, each of which can bind one ferric ion (Fe³⁺) together with a synergistic carbonate anion. Consequently, a single transferrin molecule can carry a maximum of two Fe³⁺ ions. Circulating transferrin therefore exists as apo-transferrin, monoferric transferrin, and diferric transferrin. By binding iron with high affinity, transferrin not only enables the safe transport of poorly soluble Fe³⁺ in plasma but also restricts the availability of non-transferrin-bound iron for Fenton chemistry, thereby limiting iron-mediated oxidative damage.

Transferrin-bound iron is taken up by cells primarily through transferrin receptor 1 (TfR1/CD71). Iron-loaded transferrin binds TfR1 at the plasma membrane and is internalized through clathrin-mediated endocytosis. Acidification of the endosomal compartment promotes the release of Fe³⁺ from transferrin; the iron is subsequently reduced and transported into the cytosolic labile iron pool, where it becomes available for haem synthesis, iron–sulfur cluster biogenesis, mitochondrial respiration, DNA synthesis, and other iron-dependent processes. After iron release, apo-transferrin remains associated with TfR1 under acidic conditions and is recycled with the receptor to the cell surface, where neutral extracellular pH promotes its dissociation and enables another cycle of iron transport. This pathway is particularly active in cells with high iron requirements, including erythroid precursors. A second receptor, TfR2, is expressed predominantly in the liver and contributes to the sensing of circulating transferrin-bound iron and to the regulation of systemic iron homeostasis through the hepcidin pathway.

Clinically, serum transferrin is an important parameter for evaluating iron metabolism and is closely related to total iron-binding capacity (TIBC) and transferrin saturation (TSAT). TSAT is generally calculated from serum iron and TIBC and reflects the proportion of circulating transferrin iron-binding sites that are occupied. In iron deficiency, hepatic transferrin synthesis commonly increases; consequently, serum transferrin and TIBC may rise, whereas serum iron and TSAT decrease. Conversely, persistently elevated TSAT may indicate increased systemic iron loading and is used in the screening and assessment of disorders such as hereditary haemochromatosis. Importantly, transferrin is a negative acute-phase protein. Its concentration may therefore decrease during chronic inflammation or infection, severe hepatic dysfunction, malnutrition, or protein-losing states. Serum transferrin alone does not provide an accurate measure of total body iron stores. Accordingly, clinical interpretation generally requires integration of serum iron, ferritin, TIBC, TSAT, inflammatory markers, and, where appropriate, soluble transferrin receptor (sTfR) measurements to distinguish absolute iron deficiency from inflammation-associated functional iron deficiency and iron overload.

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References

1. Cheng Y, Zak O, Aisen P, Harrison SC, Walz T. Structure of the human transferrin receptor-transferrin complex. Cell. 2004 Feb 20;116(4):565-76. doi: 10.1016/s0092-8674(04)00130-8. PMID: 14980223.