Transferrin

Overview

Transferrin is a hepatically synthesized plasma glycoprotein that binds ferric iron Fe with very high affinity and transports it safely through the bloodstream. By keeping iron soluble and tightly liganded, transferrin limits iron-driven oxidative injury while delivering iron to tissues with high metabolic demand (e.g., bone marrow, immune cells). In humans, each transferrin molecule can bind two Fe ions, and its iron-loading state (apo-, mono-, or holo-transferrin) influences receptor binding and downstream cellular handling of iron.^[1]

Cellular iron uptake: receptor-mediated endocytosis with precision recycling

Most cells acquire iron via transferrin receptor 1 (TfR1/CD71), a cell-surface protein that binds iron-loaded transferrin and internalizes the complex through clathrin-dependent endocytosis. Acidification of the endosome promotes iron release, after which transferrin (now iron-depleted) is recycled back to the plasma membrane for reuse. This pathway is tightly regulated because TfR1 abundance largely determines iron entry into cells and helps prevent iron overload.^[2][3]

Nutritional immunity and the microbiome

At mucosal surfaces and systemically, transferrin contributes to “nutritional immunity,” the host strategy of restricting microbial access to iron. By reducing free (unbound) iron, transferrin suppresses the growth of many iron-dependent bacteria and can alter which microbial taxa thrive. In experimental models, transferrin-mediated iron sequestration can directly limit pathogen fitness, illustrating that transferrin is not only a transport protein but also a host defense effector.^[4] Iron availability is a major ecological driver in the gut; changes in luminal or systemic iron can shift microbial community structure, influence inflammatory tone, and modify infection susceptibility.^[5]

Clinical interpretation: transferrin saturation as a microbiome-relevant biomarker

Clinically, transferrin is interpreted alongside serum iron and transferrin saturation (TSAT), which estimates the fraction of transferrin iron-binding sites occupied by iron. Low TSAT is typical of iron deficiency and is also common in anemia of inflammation, where the hormone hepcidin reduces intestinal iron absorption and traps iron within macrophages, effectively lowering circulating iron available for transferrin loading.^[6] Because iron distribution affects both host immunity and microbial behavior, transferrin and TSAT can be viewed as microbiome-relevant biomarkers—reflecting an iron landscape that may favor or suppress specific microbial strategies (including pathogen expansion) and shape mucosal resilience.^[7][8]

Research Feed

Update History

References

1. Human transferrin: An inorganic biochemistry perspective. Silva AMN, Moniz T, de Castro B, Rangel M.. (Coordination Chemistry Reviews. 2021)
2. Cytochrome c-549-an endogenous cofactor of cyclic photophosphorylation in the cyanobacterium Anacystis nidulans?. Kienzl PF, Peschek GA.. (FEBS Lett. 1983)
3. The transferrin receptor: the cellular iron gate. Gammella E, Buratti P, Cairo G, Recalcati S.. (Metallomics. 2017)
4. Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster. Iatsenko I, Marra A, Boquete J-P, Peña J, Lemaitre B.. (Proc Natl Acad Sci U S A. 2020)
5. Gut Microbiota and Iron: The Crucial Actors in Health and Disease. Yilmaz B, Li H.. (Pharmaceuticals (Basel). 2018)
6. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Theurl I, Aigner E, Theurl M, et al.. (Blood. 2009)
7. Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster. Iatsenko I, Marra A, Boquete J-P, Peña J, Lemaitre B.. (Proc Natl Acad Sci U S A. 2020)
8. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Theurl I, Aigner E, Theurl M, et al.. (Blood. 2009)