TF

Official Full Name

transferrin

Organism

Homo sapiens

GeneID

7018

Background

This gene encodes a glycoprotein with an approximate molecular weight of 76.5 kDa. It is thought to have been created as a result of an ancient gene duplication event that led to generation of homologous C and N-terminal domains each of which binds one ion of ferric iron. The function of this protein is to transport iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. This protein may also have a physiologic role as granulocyte/pollen-binding protein (GPBP) involved in the removal of certain organic matter and allergens from serum. [provided by RefSeq, Sep 2009]

Synonyms

TFQTL1; PRO1557; PRO2086; HEL-S-71p;

Bio Chemical Class

Transferrin

Protein Sequence

MRLAVGALLVCAVLGLCLAVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACTFRRP

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Transferrin (TF) gene is located on human chromosome 3q22.1 and encodes a glycoprotein with a molecular weight of approximately 76.5 kDa. The protein is a result of gene duplication events during evolution and contains iron-binding sites at both its N-terminal and C-terminal domains, each binding one Fe³⁺ ion. The binding process requires bicarbonate ions. This ability to bind divalent iron makes TF the central carrier for iron transport in the circulatory system. TF is highly conserved across species, with the human protein sharing 85% homology with the mouse ortholog. Its receptor-binding site is located within the C1 domain's cleft, and conformational changes in this region determine the efficiency of iron release.

Biological Function and Mechanism of Action

The core physiological function of TF is to maintain systemic iron homeostasis. It forms a stable TF-Fe³⁺ complex by binding iron absorbed from the small intestine, iron from aged red blood cells recycled by macrophages, and iron stored in liver cells. This complex is transported through the bloodstream to proliferating cells. This process depends on receptor-mediated endocytosis via Transferrin Receptor (TFRC/TFR1): after binding with the receptor on the cell surface, the complex is internalized, and iron is released in the acidic environment of the endosome. The free iron then participates in crucial processes such as hemoglobin synthesis, energy metabolism, and DNA replication. In addition to its role in iron transport, TF also has immune-modulatory functions. As a granulocyte/pollen-binding protein (GPBP), TF clears organic foreign substances and allergens from the serum and limits bacterial proliferation by restricting free iron availability. Pathogenic microorganisms, such as Neisseria, must hijack TF as an iron source to cause infection.

Figure 1. athrin-mediated endocytosi. (Kawak P, et al., 2023)

Pathophysiological Significance and Disease Associations

TF dysfunction is directly linked to hereditary hypotransferrinemia, which is characterized by abnormal iron distribution leading to iron overload in the liver and spleen, and iron deficiency in hematopoietic tissues. Clinically, it presents as severe microcytic anemia and progressive organ failure. In acquired diseases, TF acts as an acute-phase protein, and its serum levels are significantly reduced in patients with anemia of chronic disease (ACD), which is associated with interleukin-6 (IL-6)-mediated iron retention mechanisms. In the field of oncology, TFR1 (TF receptor) is overexpressed on various cancer cell surfaces, reflecting the high iron demand of tumor cells. Notably, TF dysfunction in the brain, particularly in Parkinson's disease, is associated with impaired iron transport across the blood-brain barrier (BBB), resulting in iron deposition in the substantia nigra neurons.

Clinical Applications and Translational Research

Diagnostic applications of TF primarily focus on iron metabolism assessment. Serum total iron-binding capacity (TIBC) indirectly reflects TF levels and serves as a core diagnostic marker for distinguishing between iron deficiency anemia (IDA) and ACD. Combined detection of serum iron and TF saturation improves diagnostic accuracy. In therapeutic applications, engineered TF carriers significantly enhance drug delivery efficiency. For instance, TF-conjugated liposomes (such as temozolomide nanodrug formulations) can cross the blood-brain barrier, with drug accumulation in glioblastoma models increasing threefold. TF-modified siRNA complexes target TFR1 to inhibit cyclin expression in liver cancer cells, thereby inducing tumor cell apoptosis. In the field of anti-infection strategies, blocking pathogens from utilizing TF has emerged as a new therapeutic approach. Monoclonal antibodies targeting ESAG6/ESAG7 receptors on Trypanosoma brucei can block TF-mediated iron uptake, significantly reducing parasitemia levels.

Table 1. Diagnostic Markers and Therapeutic Applications of TF-related Diseases

Disease Area	Diagnostic Marker	Therapeutic Application	Clinical Progress
Iron Metabolism Disorders	Serum TF, TIBC, TF Saturation	TF infusion therapy for hypotransferrinemia	Phase II clinical trial
Cancer Diagnosis & Therapy	Overexpression of TFR1	TF-drug conjugates for targeted delivery	Increased survival in glioma models
Infectious Diseases	Decreased serum TF levels	Anti-parasitic TF receptor antibodies	Preclinical studies

Challenges and Future Directions

The main challenge in using TF as a therapeutic carrier is the targeting efficiency reduction caused by competition from free iron, as well as the risk of exacerbating iron deficiency with prolonged use. Potential solutions include the development of iron-insensitive TF mutants (such as K206E/H207E mutants) or co-treatment with deferoxamine. Additionally, exploring non-classical iron transport pathways (such as lactoferrin and macrophage iron export) and their synergy with TF will provide new approaches for treating iron overload diseases, such as hemosiderosis.

Future research should integrate multi-omics and AI-based predictive models to better understand the role of TF in various diseases. For instance, identifying genes that collaborate with TF in repairing TACSTD2 mutations or predicting TF involvement in cancer response to antibody-drug conjugates (ADC) could lead to precision therapies. Additionally, further exploration of TF's interaction with the immune microenvironment, including co-expression with immune checkpoints (like PD-L1), could provide a foundation for combining TF-targeted ADCs with immune checkpoint inhibitors.

In conclusion, TF is a crucial molecule in iron transport, immune regulation, and cancer progression, offering potential therapeutic opportunities. However, careful modulation of its activity will be essential to maximize its clinical benefits across various disease areas.

Reference

Kawabata H. Transferrin and transferrin receptors update. Free Radic Biol Med. 2019 Mar;133:46-54.
Kawak P, Sawaftah NMA, Pitt WG, et al. Transferrin-Targeted Liposomes in Glioblastoma Therapy: A Review. Int J Mol Sci. 2023 Aug 26;24(17):13262.

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