TFRC

Detailed Information

The TFRC (Transferrin Receptor 1) gene is located on human chromosome 3q29 and encodes a type II transmembrane glycoprotein (CD71) that plays a crucial role in cellular iron uptake. This receptor consists of two homologous subunits connected by disulfide bonds, with each monomer containing an extracellular domain, a single transmembrane region, and a short cytoplasmic tail. The extracellular domain contains sites for specific binding to transferrin (Tf), forming a Tf-TFR1 complex that mediates endocytic transport of iron ions. Under physiological conditions, TFRC is expressed in almost all cell types, but its expression is notably higher in tissues with greater iron demand, such as the hematopoietic system (e.g., bone marrow stem cells, erythroid progenitors), liver, and placenta. This widespread and tissue-specific expression pattern underscores the central role of iron in essential cellular processes like cell proliferation, oxygen transport, and energy metabolism.

TFRC-mediated iron uptake is a tightly regulated process: plasma divalent iron ions (Fe³⁺) bind to transferrin to form holo-Tf complexes. These complexes bind to TFRC on the cell surface and are internalized into endosomes via clathrin-coated pits. As the endosome acidifies to pH 5.5, iron is released from transferrin and transported into the cytoplasm via the divalent metal transporter DMT1. The apo-Tf (iron-free transferrin) remains bound to TFRC, which recycles to the cell surface where it dissociates in a neutral pH environment, completing the cycle. This process can be repeated hundreds of times per hour, ensuring that cells have a sufficient iron supply. Notably, TFRC expression is finely regulated by intracellular iron levels: when iron is abundant, iron regulatory proteins (IRPs) bind to iron response elements (IREs) in the TFRC mRNA, inhibiting its translation. Conversely, when iron is scarce, the IRP-IRE complex dissociates, increasing TFRC synthesis and forming a negative feedback loop.

In addition to its role in iron uptake, recent studies have revealed non-classical functions of TFRC. As a lipid sensor, TFRC can sense stearic acid (C18:0) levels and regulate JNK signaling, which influences the ubiquitination and degradation of the mitochondrial fusion protein MFN2, thereby modulating mitochondrial dynamics. When dietary stearic acid levels are low, TFRC promotes JNK pathway activation, leading to HUWE1-mediated degradation of MFN2, inhibiting mitochondrial fusion. In contrast, under high stearic acid conditions, TFRC palmitoylation inhibits JNK signaling, stabilizing MFN2 and promoting mitochondrial fusion. Furthermore, TFRC acts as a cellular receptor for several viruses, including New World arenaviruses such as Guanarito, Junin, and Machupo, playing a key role in pathogen invasion. In the nervous system, TFRC regulates the transport of the metabotropic glutamate receptor mGlu1, affecting cerebellar motor coordination, thus expanding our understanding of TFRC's biological functions.

Figure 1. Regulation of TFRC transcription. (Shen Y, et al., 2018)

Association with Tumors and Diseases

TFRC exhibits abnormal expression in a variety of pathological conditions, particularly in malignant tumors. Tumor cells, to meet the demands of rapid proliferation, significantly increase their iron intake, leading to TFRC upregulation and the phenomenon of "iron addiction." In colorectal cancer, TFRC expression is significantly higher than in normal mucosal tissue, and its mediated iron uptake activates Tankyrase (TNKS) enzyme activity, promoting Axin2 degradation and thereby activating the Wnt/β-catenin signaling pathway to drive tumorigenesis. Moreover, iron overload can upregulate c-Myc expression and enhance DNA polymerase delta 1 (POLD1) expression via the transcription factor E2F1, maintaining genomic stability. TFRC deficiency triggers DNA replication stress, accumulation of damage, and apoptosis. Research from the University of New Mexico confirmed that inactivating TFRC genetically significantly prolonged the survival of colorectal cancer model animals, providing a proof of concept for targeting TFRC in anticancer strategies.

In the field of gastric cancer, a clinical study involving 112 patients revealed that the positive expression rate of TFRC protein in gastric cancer tissue was 67.86%, significantly higher than in adjacent non-cancerous tissue (21.43%). The TFRC mRNA positivity rate was 60.71%, far exceeding that of adjacent tissue (15.18%). Importantly, overexpression of TFRC was significantly associated with poor pathological features such as a tumor size ≥5 cm, late clinical stages (III-IV), poor differentiation, deep muscular invasion (T3+T4), and lymph node metastasis. Mechanistically, high TFRC expression activates the IL-6/IL-11-STAT3 signaling pathway, promoting tumor cell proliferation and inhibiting apoptosis, thereby accelerating gastric cancer progression. Similar phenomena have been reported in various other cancers, including thyroid, esophageal squamous cell carcinoma, breast, liver, leukemia, lung, pancreatic, and nasopharyngeal cancers, suggesting that TFRC overexpression is a common feature of tumors.

In non-tumor diseases, abnormal TFRC expression also has significant pathological implications. In neurodegenerative diseases, disrupted brain iron metabolism is closely linked to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In Alzheimer's disease patients, TFRC expression is abnormally elevated in the temporal cortex, leading to neuronal iron overload, which catalyzes reactive oxygen species (ROS) generation, induces oxidative stress, and accelerates β-amyloid deposition and Tau hyperphosphorylation. Studies in animal models suggest that inhibiting TFRC expression can alleviate brain iron overload, offering new prospects for neuroprotection. In hematological disorders, TFRC, as a key regulator of erythropoiesis, is significantly upregulated in patients with iron-deficiency anemia and β-thalassemia. Research in thalassemia mouse models has shown that reducing TFRC expression in erythroid progenitor cells can effectively regulate ineffective erythropoiesis and improve anemia and iron overload. Furthermore, TFRC has been identified as a functional receptor for the hepatitis C virus (HCV), mediating viral fusion with host cell membranes during HCV invasion, offering a potential therapeutic target for antiviral treatment.

Clinical Translation and Therapeutic Prospect

Targeted therapeutic strategies targeting TFRC are rapidly evolving, covering monoclonal antibodies, antibody-drug conjugates (ADCs), gene silencing technologies, and blood-brain barrier penetration-enhancing systems. In cancer treatment, anti-TFRC monoclonal antibodies like JST-TFR09 and A24 exert antitumor effects by blocking iron uptake pathways or inducing apoptotic signals. JST-TFR09 effectively inhibits tumor cell iron intake, while A24 specifically induces apoptosis in T-cell leukemia malignant cells. The ADC CX-2029 links an anti-TFRC antibody with a cytotoxic drug for targeted delivery, with ongoing clinical trials for diffuse large B-cell lymphoma entering Phase I/II. In the field of genetic blood disorders, PPMX-T003, an anti-TFRC antagonist, is currently undergoing Phase I/II clinical trials for large granular lymphocyte leukemia and polycythemia vera.

Iron chelators, as indirect regulators of TFRC function, show potential in cancer therapy. The University of New Mexico team is exploring the use of iron chelators (such as deferoxamine) to selectively deplete tumor cell iron reserves, inducing DNA damage and apoptosis. Laboratory studies suggest that combining iron chelation with DNA damage repair inhibitors can generate synergistic antitumor effects, offering a new approach for colorectal cancer treatment. In gastric cancer, TFRC-negative patients showed significantly higher sensitivity to chemotherapy drugs like cisplatin, cyclophosphamide, fluorouracil, and methotrexate compared to TFRC-positive patients. More importantly, TFRC positivity in gastric cancer tissues was significantly lower in chemotherapy-sensitive patients than in the resistant group, suggesting that TFRC expression may serve as an independent predictor of chemotherapy sensitivity, providing a potential molecular marker for personalized treatment.

In the treatment of neurological disorders, TFRC, a highly expressed receptor at the blood-brain barrier (BBB), is widely used in designing brain-targeted drug delivery systems. Antibodies like Trontinemab, designed as bispecific antibodies, bind to TFRC to facilitate BBB penetration while targeting brain lesion proteins (such as β-amyloid), significantly improving drug delivery efficiency to the brain. This strategy shows therapeutic potential in Alzheimer's disease clinical trials. Similarly, the DYNE-251 therapy for Duchenne muscular dystrophy uses an anti-TFRC antibody to deliver gene therapy drugs to the central nervous system, currently undergoing Phase I/II clinical trials.

Despite the promising therapeutic prospects of TFRC targeting, several challenges remain. First, the essential physiological role of TFRC demands highly selective therapeutic strategies to avoid adverse effects such as anemia and immune suppression caused by systemic iron deficiency. Second, the iron metabolism regulatory network in the tumor microenvironment is complex, involving various transporters (e.g., DMT1, Ferroportin) and regulators (e.g., hepcidin). Targeting TFRC alone may not fully block iron acquisition by tumor cells. Additionally, the iron metabolism characteristics vary across tumor types, requiring the development of personalized biomarkers to guide therapy. Future research should integrate nanotechnology to develop tumor-specific TFRC inhibitors, explore TFRC expression levels as predictive markers for treatment response, and design more precise iron chelation delivery systems that can inhibit tumor growth while preserving normal cell function.