The transferrin receptor: the cellular iron gate Original paper

What was reviewed?

This review on transferrin receptor 1 iron uptake summarizes how transferrin receptor 1 (TfR1; CD71) functions as the main cellular “gate” for importing transferrin-bound iron and how its expression is tightly regulated to prevent iron deficiency or iron overload. The authors describe the canonical pathway in which diferric transferrin binds TfR1, is internalized via clathrin-mediated endocytosis, releases iron in acidified endosomes, and then recycles the apo-transferrin-TfR1 complex back to the cell surface (illustrated schematically in the figures and legends). They emphasize that regulation of TfR1 abundance at the plasma membrane is rate-limiting for cellular iron entry and is therefore controlled at multiple levels, including post-transcriptional (iron-responsive element/iron regulatory protein signaling), transcriptional (hypoxia-inducible factors and proliferative transcription factors), and post-translational trafficking/degradation mechanisms. Although not a microbiome paper, this framework is clinically relevant to microbiome science because iron availability is a dominant ecological pressure shaping gut microbial composition and pathogen expansion, and host iron-handling proteins can indirectly define microbiome “signatures” associated with inflammation, infection risk, or anemia states.

Who was reviewed?

The paper is a mechanistic, host-focused review and does not analyze a single cohort; instead, it synthesizes evidence from diverse experimental systems. The reviewed literature spans cell biology and structural studies of TfR1 and the transferrin–TfR1 complex, animal models with tissue-specific TfR1 deletion (e.g., heart, skeletal muscle, dopaminergic neurons, intestinal epithelium), and human disease observations where TfR1 regulation intersects with anemia, iron overload syndromes, cancer metabolism, and immunodeficiency linked to TFRC variants. It also discusses erythroid precursors (where TfR1 is highly expressed to support hemoglobin synthesis), rapidly proliferating malignant and non-malignant cells, hepatocytes (in systemic iron signaling contexts involving HFE/TfR2), and immune cells, highlighting that TfR1 biology is tissue- and context-dependent. For microbiome-informed clinical interpretation, these host populations matter because changes in systemic iron trafficking (e.g., hepcidin–ferroportin axis, transferrin saturation, non-transferrin-bound iron formation) can alter luminal iron exposure and thereby shift microbial community structure toward iron-scavenging taxa or opportunistic Enterobacteriaceae during inflammation.

Most important findings

A central message is that TfR1 expression is governed primarily by the IRP/IRE system: low intracellular iron increases IRP binding to IREs in the TfR1 mRNA 3′UTR, stabilizing the transcript and boosting receptor levels, whereas iron repletion reduces IRP binding and promotes mRNA degradation, thereby limiting iron uptake. The review highlights newly described control points, including Regnase-1 as an endoribonuclease targeting TfR1 mRNA, and modulatory roles for mTOR–tristetraprolin and specific microRNAs (e.g., miR-320, miR-152) that tune TfR1 expression. At the transcriptional level, hypoxia and iron deficiency converge via HIF signaling to induce TfR1 transcription, while proliferative pathways (e.g., c-Myc, AP-1, Stat5 in erythropoiesis) further upregulate TfR1 to meet iron demands. Post-translationally, TfR1 trafficking is not purely constitutive: iron excess can bias TfR1 toward lysosomal degradation (including via MARCH8-mediated ubiquitination), while other signaling inputs can redistribute TfR1 to the cell surface. Beyond iron delivery, TfR1 may have iron-independent signaling roles and is exploited as an entry factor by multiple viruses—an insight relevant to infection susceptibility in iron-altered states. For microbiome signature databases, the practical takeaway is that host iron uptake regulation can be treated as a “host-context layer” that predicts microbial shifts toward iron acquisition strategies, potentially amplifying dysbiosis during iron supplementation, bleeding, or inflammation.

Key implications

Clinically, this review reframes TfR1 as a precision-controlled gateway whose dysregulation can contribute to anemia, iron overload, immune dysfunction, cardiomyopathy, neurodegeneration, and cancer growth, while also providing a mechanistic rationale for TfR1-targeted therapies (antibodies, transferrin-drug conjugates) and for interpreting soluble TfR1 as a marker of erythropoietic drive and iron need. From a microbiome-informed perspective, the work underscores why host iron partitioning—not just dietary iron—should be considered when evaluating microbiome signatures linked to inflammatory bowel disease, enteric infection susceptibility, or response to iron supplementation: shifts in transferrin saturation, hepcidin activity, and TfR1-regulated cellular uptake can change how much bioavailable iron reaches the gut lumen, which can selectively favor iron-scavenging taxa and promote expansion of opportunistic pathogens. Integrating host iron-uptake state (including TfR1 biology) alongside microbial composition can therefore sharpen clinical interpretation of “dysbiosis” patterns and help explain why similar microbiome profiles can associate with different iron phenotypes across patients.

Citation

Gammella E, Buratti P, Cairo G, Recalcati S. The transferrin receptor: the cellular iron gate. Metallomics. 2017. doi:10.1039/C7MT00143F