Transferrin Receptor Biology in Iron Metabolism

Iron is indispensable for oxygen transport, DNA synthesis and energy production, yet free iron is potentially toxic. Cellular uptake of iron is primarily mediated by the transferrin receptor (TfR), which binds circulating transferrin loaded with ferric iron and internalises it via receptor-mediated endocytosis. Two principal isoforms, TfR1 and TfR2, exhibit distinct tissue distributions and regulatory mechanisms: TfR1 is ubiquitously expressed and tightly controlled by intracellular iron‐responsive proteins, whereas TfR2, enriched in hepatocytes, plays a specialised role in systemic iron sensing and signalling to the hormone hepcidin. Expression of both receptors is further modulated by hypoxia-inducible factors and by post-transcriptional regulators such as microRNAs. At the systemic level, hepcidin governs iron release from enterocytes and macrophages by inducing degradation of ferroportin, thus coupling uptake to export and maintaining whole-body homeostasis. Dysregulation of transferrin receptor biology underlies disorders from iron-loading anaemias and hereditary haemochromatosis to chronic inflammation and malignancy, where elevated TfR1 supports rapid proliferation and offers a conduit for targeted therapies.

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Transferrin Receptor Biology in Iron Metabolism publication trend

The graph below shows the total number of articles in transferrin receptor biology in iron metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Transferrin receptor (TfR): A cell‐surface glycoprotein that binds iron‐loaded transferrin and mediates its internalisation.

Receptor‐mediated endocytosis: The selective uptake of extracellular ligands through binding to specific membrane receptors followed by vesicular internalisation.

Ferroptosis: A regulated form of cell death driven by iron‐dependent lipid peroxidation and distinct from apoptosis or necrosis.

Autophagy: A lysosome-dependent pathway that degrades intracellular components, including organelles and membrane proteins, to maintain cellular homeostasis.

Hepcidin: A liver-derived peptide hormone that controls systemic iron balance by promoting the internalisation and degradation of the iron exporter ferroportin.

References

1. Transferrin receptors. Experimental & Molecular Medicine (2025).
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3. Iron homeostasis: An anthropocentric perspective. Journal of Biological Chemistry (2017).
4. Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents. Frontiers in Immunology (2021).
5. Hepcidin: regulation of the master iron regulator. Bioscience Reports (2015).
6. Transferrin Receptor Induction by Hypoxia HIF-1-MEDIATED TRANSCRIPTIONAL ACTIVATION AND CELL-SPECIFIC POST-TRANSCRIPTIONAL REGULATION*. Journal of Biological Chemistry (1999).
7. MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis. Oncotarget (2015).
8. Hereditary Hemochromatosis Protein, HFE, Interaction with Transferrin Receptor 2 Suggests a Molecular Mechanism for Mammalian Iron Sensing*. Journal of Biological Chemistry (2006).