Transferrin receptor 1: an emerging therapeutic target in cancer beyond iron metabolism

Abstract

Iron is an indispensable trace element for maintaining normal physiological functions in the body, participating in key biological processes such as energy metabolism, DNA synthesis, and damage repair. Under normal physiological conditions, cells tightly regulate iron homeostasis to prevent iron overload-induced oxidative stress and DNA damage. In contrast, tumor cells undergo iron metabolic reprogramming to adapt to their aberrant proliferation and elevated metabolic levels. By upregulating iron uptake and storage pathways, they elevate intracellular iron levels, providing essential cofactors for accelerated DNA synthesis and mitochondrial energy production, thereby meeting the material and energy demands of malignant growth. As an essential regulator of iron acquisition, transferrin receptor 1 (TFR1) binds transferrin (TF) and enters the cell through clathrin-mediated endocytosis to deliver ferric iron (Fe³⁺). Internalized TFR1 returns to the cytoplasmic membrane via the recycling pathway, sustaining surface receptor levels and enabling continued iron uptake. Owing to this mechanism, TFR1 has emerged as a prominent target for anticancer drug development. This review focuses on the molecular mechanisms regulating TFR1, from transcriptional regulation to translational expression, with a focus on its biological roles in iron metabolism and malignant progression. Furthermore, we summarize various TFR1-targeted antitumor strategies based on current research, providing a theoretical foundation for the development of novel anticancer therapeutics.

Introduction

In the physiological environment, iron mediates redox reactions through reversible electron transfer (Fe²⁺ ⇌ Fe³⁺ + e⁻) and is an essential trace element for processes such as DNA synthesis and repair, energy production, and oxygen transport [1, 2]. Intracellular iron metabolism is tightly regulated, and disruption of its homeostasis can lead to severe consequences. For instance, iron deficiency impairs the activity of mitochondrial electron transport chain (ETC) complexes, thereby reducing adenosine triphosphate (ATP) synthesis, and compromises immune cell function [3]. In contrast, iron overload promotes the generation of free radicals via the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + ·OH + OH⁻), which induces lipid peroxidation (LPO) and tissue damage [4]. Compared with healthy cells, cancer cells require higher levels of iron to sustain their rapid proliferation rate and elevated metabolic demands [5–7]. When iron supply is insufficient, it can block DNA synthesis in cancer cells, inhibit proliferation, and trigger apoptosis [8].

TFR1, a key molecule that mediates the cellular uptake of Fe³⁺, is frequently overexpressed in various cancers [9, 10]. TFR1 is a type II transmembrane glycoprotein of 760 amino acids that forms a disulfide-linked homodimer of ~ 180 kDa on the cell surface [11]. The protein is composed of an N-terminal cytoplasmic domain (residues 1–67), a transmembrane region (residues 68–88), and a C-terminal extracellular domain (residues 89–760). Upon the binding of holo-transferrin (holo-TF) to cell-surface TFR1, the TF–TFR1 complex is internalized via clathrin-mediated endocytosis, a process that depends on the adaptor protein 2 complex and dynamin [12]. Internalized vesicles mature into acidic endosomes. The ATP-dependent proton pumps on the endosomal membrane pump H⁺ into the lumen, lowering the pH to approximately 5.5. This induces conformational changes in TF, reduces its binding affinity for Fe³⁺, and promotes the release of Fe³⁺ [13]. Meanwhile, TFR1 is recycled back to the plasma membrane to sustain continuous iron transport.

With this unique endocytic recycling property, TFR1 stands out as a strategic target for anticancer therapy, with groundbreaking advances achieved in areas such as targeted drug delivery systems and protein degradation therapies [14, 15]. Based on these characteristics, this review summarizes the molecular regulatory mechanisms of TFR1 and explores the clinical translational value of emerging TFR1-targeted antitumor strategies.

Genomic alternations, transcriptional and post-transcriptional mechanisms regulating TFR1 expression

Transcriptional regulation of TFR1

TFR1 encodes a pivotal membrane protein responsible for regulating cellular iron uptake [16–18]. The gene expression of TFR1 is precisely regulated by multiple transcription factors. For example, hypoxia-inducible factor 1 (HIF-1) plays an essential role in various physiological and pathological processes such as hypoxia adaptation, metabolic reprogramming and angiogenesis. HIF-1 drives TFR1 expression by binding to the hypoxia response element in its promoter region [19, 20]. Additionally, as the core downstream effectors of the Hippo signaling pathway, Yes-associated protein/tafazzin (YAP/TAZ) maintain cell proliferation and differentiation by reprogramming various cellular metabolic pathways and are highly sensitive to microenvironmental changes [21]. YAP has been demonstrated to drive TFR1 expression in multiple cancer types. For instance, in breast cancer, Merlin binding to lncRNA LncRIM disrupts its interaction with large tumor suppressor kinase 1 (LATS1), thereby inhibiting LATS1 activation [22]. This leads to dephosphorylation and nuclear translocation of YAP, which promotes TFR1 transcription and facilitates iron metabolic reprogramming in cancer cells [23]. Similar observations were reported in prostate and liver cancers, the deubiquitination and o-glcnacylation modifications of YAP drive the expression of TFR1 [24, 25]. Transforming growth factor-beta (TGF-β) enhances the nuclear localization of the transcriptional coactivator TAZ, which subsequently forms a transcriptional complex with YAP and TEA domain transcription factor 4 to drive TFR1 mRNA transcription (Fig. 1) [26].

Fig. 1.

Schematic representation of the transcriptional regulatory network governing TFR1 DNA expression. The abundance of TFR1 is regulated by multiple transcription factors

In addition to transcriptional regulation, the expression of TFR1 is modulated by various epigenetic modifications. The enrichment of histone H3 lysine 4 dimethyl (H3K4me2) at the TFR1 promoter, which facilitates transcription, can be erased by lysine-specific demethylase 1 (LSD1) [27]. Lactylated LSD1 interacts with Fos-like antigen 1 (FosL1), thereby blocking tripartite motif-containing protein 21 (TRIM21)-mediated FosL1 degradation [28]. This synergistic action suppresses TFR1-mediated iron uptake and promotes drug resistance in tumors. The TFR1 locus is also subject to Histone H3 lysine 9 trimethylation (H3K9me3) modification, which is catalyzed by the SET domain bifurcated histone lysine methyltransferase 2 (SETDB2) and contributes to its transcriptional silencing [29]. Elevated intracellular iron levels can also activate suppressor of variegation 3–9 homolog 1, which catalyzes the formation of H3K9me3 to suppress the expression of the TFR1 gene [30]. In addition to the histone methylation modifications mentioned above, Histone H3 lysine 14 lactylation (H3K14la) modification has recently been identified at the TFR1 promoter region [31]. The potential roles and regulatory mechanisms of other modifications, such as acetylation-related marks, remain to be elucidated.

RNA-based control of TFR1 expression

m⁶A epigenetic modification regulation

N(6)-methyladenosine (m⁶A) methylation is the most prevalent internal posttranscriptional modification on mammalian RNA and dynamically regulates gene expression through epigenetic writer-eraser-reader system [32, 33]. The m⁶A modification on TFR1 RNA is primarily catalyzed by the METTL3/METTL14 methyltransferase complex, which functions as the Writer enzyme. The Erasers are primarily represented by the demethylases fat mass and obesity associated (FTO) and alkylation repair homolog protein 5 (ALKBH5), which dynamically remove m⁶A modification. This activity is particularly enhanced under stress conditions such as hypoxia [34]. Meanwhile, the Reader function is primarily executed by proteins such as YTHDF1/2/3 and IGF2BP2, which mediate diverse downstream effects including promoting mRNA translation, degradation or stability [35]. The system precisely coordinates to control gene expression. For example, doxorubicin induces METTL3 via c-Jun to catalyze m⁶A modification of TFR1 RNA [36]. This modification is recognized by YTHDF3, which increases TFR1 mRNA stability [37]. In colorectal cancer, METTL4-mediated m⁶A modification of TFR1 RNA is recognized by IGF2BP2, enhancing mRNA stability, promoting iron-metabolic reprogramming, and driving tumor progression [38]. During organ injury, FTO is typically down-regulated. Subsequently, TFR1 mRNA is stabilized by YTHDF1, aggravating organ damage [34, 39]. YTHDF1 interacts with the 3’UTR and 5’UTR of TFR1 mRNA, positively regulating m⁶A modification and thereby promoting the translation of TFR1 mRNA in hypopharyngeal squamous cell carcinoma [35].

Alternative splicing and circRNA-mediated regulation

TFR1 pre-mRNA can produce circular RNAs (circRNAs) through back-splicing events. The circRNA hsa_circ_0068631, derived from exons 2 and 3 of TFR1, recruits EIF4A3 to increase c-Myc mRNA stability, and the similar mechanism has been documented in both breast and ovarian cancers [40, 41]. Exons 12–14 of TFR1 further generate cTFR1, which accelerates TGF-β–induced epithelial–mesenchymal transition in bladder carcinoma progression [42]. Additionally, another splicing variant of TFR1 was discovered, which skips exon 4 and disrupts the normal function of TFR1 in endometrial cancer [43].

miRNA and ceRNA network regulation

The abundance of TFR1 mRNA is also regulated by other post-transcriptional regulatory mechanisms. MicroRNAs (miRNAs) regulate target mRNAs through microRNA response elements (MREs) [44]. For example, miR-148a directly regulates the expression of TFR1 mRNA by binding to MREs in the 3’UTR of TFR1 mRNA in hepatocellular carcinoma (HCC) [45]. Some miRNAs demonstrate an iron-sensing function. Under conditions such as iron deficiency and hypoxia, upregulated miR-210 precisely regulates TFR1 expression to stimulate cell proliferation and promote survival in hypoxic tumor regions, thereby contributing to the maintenance of iron homeostasis [46]. Long non-coding RNAs (LncRNAs) and circRNAs act as competing endogenous RNAs (ceRNAs) by sponging miRNAs. In glioblastoma, lncRNA RP1-86C11.7 sponges hsa-miR-144-3p, thereby attenuating its binding to TFR1 and accelerating disease progression [47]. The up-regulated circPIK3C2A sponges miR-31-5p, relieving its inhibition of TFR1 and thereby triggering cell death [48].

IRP/IRE and other mRNA stability regulatory mechanisms

Iron-Regulatory Protein 1/2 (IRP1/2), the master sensors of cellular iron status, bind to the IRE in TFR1 mRNA and modulate its stability. Under iron-sufficient conditions, the majority of IRP1 exists in a form that contains an intact [4Fe-4S] iron-sulfur cluster. In this state, IRP1 functions as a cytosolic aconitase, participates in the tricarboxylic acid cycle, and loses its IRE-binding activity [49]. Signaling molecules such as nitric oxide and reactive oxygen species (ROS) facilitate the disassembly of the [4Fe-4S] cluster, leading to the conversion of IRP1 into its IRE-binding form and consequently enhancing the stability of TFR1 mRNA [50]. This mechanism has been validated in pancreatic cancer [51]. Unlike IRP1, IRP2, as the main regulator of iron metabolism, can sense the deficiency of iron-sulfur clusters and its function is independent of IRP1 [52, 53]. KLF14 directly binds to the IRP2 promoter and recruits the deacetylase Sirtuin 1, thereby repressing IRP2 transcription. This restricts TFR1 protein synthesis, driving iron depletion and growth arrest in HCC cells [54]. In FGFR1-deficient prostate cancer, overexpressed IRP2 restores the tumorigenic activity of the cancer cells by stabilizing TFR1 mRNA [55]. Besides IRP1/2, mTOR also regulates TFR1 expression. As the downstream target of mTOR signaling, tristetraprolin binds to AU-rich elements in the 3’ UTR of TFR1 mRNA and recruits an exonuclease complex to degrade it [56]. Furthermore, TFR1 mRNA can also be directly recognized by the endonuclease Regnase-1, which promotes its mRNA degradation (Fig. 2) [57].

Fig. 2.

Schematic representation of the multi-level regulatory mechanisms governing TFR1 gene expression during post-transcriptional processing

Post-translational modifications of TFR1

TFR1 possesses multiple post-translational modification (PTM) sites, including three N-glycosylation sites at asparagine residues 251/317/727, two O-glycosylation sites at Thr104/Ser687, two S-palmitoylation sites at Cys62/67, one SUMOylation site at Lys95, etc [11]. These dynamic modifications collectively regulate the TFR1 protein stability and biological functions. For instance, O-glycosylation at the Thr104 site of TFR1 can prevent protease cleavage and suppress soluble TFR1 formation [58]. Senyilmaz et al. discovered that dietary-derived stearic acid (C18:0) can covalently bind to cysteine residues of the TFR1 protein via thioester linkage. Stearoylation inhibits JNK signaling, reduces dynamin-1-like protein phosphorylation and E3 ubiquitin ligase HUWE1-mediated mitofusin degradation, thereby promoting mitochondrial fusion and functional enhancement [59].

Beyond the above canonical modifications, ubiquitination serves as another pivotal post-translational mechanism that regulates TFR1 protein turnover. This process is precisely controlled by multiple E3 ubiquitin ligases. Specifically, the tribbles pseudokinase 2 (TRIB2) facilitates beta-transducin repeat containing protein (βTrCP)-mediated ubiquitination and degradation of TFR1, thereby reducing intracellular labile iron levels and conferring resistance to ferroptosis. Even when glutathione peroxidase 4 (GPX4) is inhibited, TRIB2 still regulates ferroptosis via the TFR1/βTrCP axis to exert a protective effect [60]. As another E3 ubiquitin ligase, carboxyl terminus of Hsc70-interacting protein knockdown stabilizes TFR1 which leads to intracellular Fe²⁺ accumulation and ultimately inhibiting cancer cell growth [61]. Additionally, the NEDD4L-dependent ubiquitin-proteasome pathway has been found to promote TFR1 degradation and its upregulation affects the prognosis of patients with endometrial cancer [62]. Notably, in HCC, treatment with the ferroptosis inducer erastin triggers de-O-GlcNAcylation at the Ser687 site of the TFR1 protein. This modification attenuates the binding of the E3 ubiquitin ligase membrane-associated RING-CH 8 to TFR1, reducing TFR1 polyubiquitination at Lys665 and thereby shielding TFR1 from subsequent ubiquitin-dependent degradation [63]. Certain site-specific PTMs can hinder the recruitment of E3 ubiquitin ligases, attenuate the ubiquitination of TFR1, and inhibit its degradation, thereby maintaining intracellular TFR1 protein homeostasis. This regulatory mechanism may further affect cellular iron homeostasis, mitochondrial function, and ferroptosis sensitivity, ultimately modulating tumor progression.

In summary, a thorough understanding of TFR1 regulation across genetic, transcriptional, and translational levels can lay the foundation for developing novel therapeutic targets for cancerous diseases.

The biological characteristics of TFR1

TFR1-mediated iron uptake

The primary ligands of TFR1 are transferrin (TF), ferritin, hepcidin, etc [64]. Among them, TF is the primary TFR1 ligand, with each molecule binding two ferric ions to form the core of iron transport. Following iron binding, TF undergoes a conformational transition from an open to a closed state. After TF binds to TFR1, an adaptor protein recognizes the endocytic motif within the intracellular domain of TFR1, facilitating the recruitment of TFR1 into clathrin-coated vesicles. Subsequently, with the assistance of endocytic accessory proteins, the vesicles are internalized [65, 66]. After internalization, the vesicles undergo an uncoating process and subsequently mature into early endosomes. The pH within the endosomes gradually decreases, leading to a conformational change in TF. This causes the release of its bound Fe³⁺. The Fe³⁺ is then reduced to Fe²⁺ by Six-transmembrane epithelial antigen of the prostate family and is ultimately transported into the cytoplasm via the divalent metal transporter 1 (DMT1) to participate in various iron-dependent biological functions [67]. Upon entering the cytoplasm, iron enters the labile iron pool (LIP), a compartment of weakly chelated, redox-active Fe²⁺. The subsequent trafficking of this iron is critical to understanding the form and function of excess iron in cancer cells.

In cancer cells, surplus iron is not present in a single form but is instead partitioned primarily into two pools. The first is the LIP itself, where Fe²⁺ can directly participate in Fenton reactions to generate ROS. Although this redox activity can be cytotoxic, cancer cells typically evade damage by upregulating antioxidant systems such as GPX4. Ferroptosis is only triggered when iron overload surpasses the cellular antioxidant buffering capacity or when GPX4 is pharmacologically inhibited. Ferritin-bound Fe³⁺ represents another, more stable mode of iron storage. The ferritin storage system appears hyperactivated in many cancers, not as a passive overflow mechanism, but as an active survival strategy [68]. Cancer cells often exhibit a defect in the non-autophagic degradation pathway of ferritin, which allows them to maintain an elevated ferritin reserve. This reserve functions dually: its heavy chain (FTH) directly promotes survival through inherent antioxidant activity and by inhibiting TNFα-induced apoptosis, while the iron stored within the ferritin cage serves as a rapidly mobilizable resource. Upon demand, ferritin is degraded by nuclear Receptor Coactivator 4-mediated ferritinophagy in the lysosome, releasing Fe²⁺ back into the LIP [69]. Therefore, the storage of iron as ferritin is critical for growth precisely because it constitutes a resilient, self-replenishing buffer that can supply the LIP with the iron needed for essential processes like DNA synthesis while simultaneously guarding against both iron-mediated oxidative stress and apoptosis.

Crucially, a significant portion of the iron from the LIP does enter the mitochondria via chaperones such as poly(rC)-binding protein 2 to support the synthesis of iron-sulfur clusters and heme, which are essential cofactors for the ETC [70]. This has raised the question of whether this iron-fortified mitochondrial activity, which generates ATP through oxidative phosphorylation (OXPHOS), would counteract the Warburg effect—the preference for aerobic glycolysis typical of cancer cells. Current evidence suggests that these two metabolic modes are not mutually exclusive but are complementary. The Warburg effect remains a dominant feature, especially in highly malignant, hypoxic, or drug-resistant cells, as it rapidly provides biosynthetic precursors for proliferation and lactate to condition the microenvironment. Iron-mediated enhancement of mitochondrial ATP generation serves as an adaptive supplement rather than a replacement [71]. For instance, under hypoxic conditions, HIF-1 transcriptionally upregulates TFR1, and the resulting iron influx is partially directed to sustain mitochondrial function, helping the cell adapt to oxygen deprivation and maximize oxygen utilization efficiency [72]. When cellular iron demand decreases or cells are under oxidative stress defense, ferroportin-1 mediates the efflux of intracellular Fe²⁺, excreting excess iron out of the cell and releasing it into the blood circulation (Fig. 3).

Fig. 3.

Schematic representation of TFR1 endocytosis and iron transport. Following internalization, TFR1 can be recycled back to the plasma membrane or targeted for lysosomal degradation. Excess iron is stored as Fe³⁺ within ferritin nanocages. Under conditions of cellular iron overload, excess iron catalyzes membrane lipid peroxidation through the Fenton reaction, ultimately leading to ferroptosis

In addition to TFR1, mammalian cells possess other iron uptake pathways, such as transferrin receptor 2 and zinc transporter protein 8/14. TFR1 is ubiquitously expressed at low levels in healthy cells, with high expression limited to highly proliferative or iron-demanding tissues; in contrast, TFR2 is largely confined to the liver, and non-hepatic cells exhibit minimal dependence on it. Owing to their rapid proliferation, cancer cells exhibit an “iron addiction” phenotype [73]. Tumor cells are far more dependent on TFR1 for maintaining iron homeostasis than their normal counterparts, and the compensatory capacity of alternative transport pathways is markedly limited [73, 74]. Given that functional studies have demonstrated that targeting TFR1 significantly depletes the LIP in cancer cells and exhibits potent antitumor activity in multiple xenograft models, it is foreseeable that the disruption of iron homeostasis caused by TFR1 inhibition will far exceed the compensatory capacity of other transporters [72, 75].

TFR1 and ferroptosis

To meet the substantial iron demands for proliferation, damage repair, and metastasis, cancer cells typically upregulate transferrin receptor expression, thereby enhancing iron uptake capacity. When intracellular iron levels far exceed the cellular utilization and storage capacity, iron homeostasis is disrupted, leading to a marked elevation of free Fe²⁺ in the LIP. These free Fe²⁺ ions can react with metabolically generated hydrogen peroxide (H₂O₂) through the Fenton reaction, producing excessive highly reactive hydroxyl radicals [76]. These radicals attack polyunsaturated fatty acids (PUFA) in membrane phospholipids, initiating LPO and resulting in the massive accumulation of lipid hydroperoxides (LOOH), which subsequently triggers characteristic mitochondrial damage, including cristae fragmentation and outer membrane rupture [77]. Such structural impairments disrupt oxidative phosphorylation and promote massive ROS production, further amplifying oxidative stress. Concurrently, excess Fe²⁺ interferes with the assembly of mitochondrial iron-sulfur clusters and heme prosthetic groups, compromising ETC function and causing electron leakage and increased superoxide anion (·O₂⁻) generation; the latter is subsequently converted to H₂O₂, thereby perpetuating a vicious cycle of oxidative stress [78]. This iron-dependent programmed cell death modality, driven by iron metabolic imbalance and characterized by lipid peroxidation and mitochondrial damage as its core features, is known as ferroptosis.

To resist ferroptosis, cancer cells activate multiple defense mechanisms, among which the amino acid metabolism pathway and the lipid metabolism pathway are particularly critical [79]. In the amino acid metabolism pathway, cancer cells highly express system Xc⁻ to actively take up extracellular cystine. Upon entering the cell, cystine is reduced to cysteine, which serves as the rate-limiting substrate for glutathione (GSH) synthesis. GSH is an essential cofactor for GPX4 to scavenge lipid peroxides; abundant GSH maintains GPX4 activity, thereby effectively blocking the lipid peroxidation chain reaction. Additionally, in the lipid metabolism pathway, GPX4 utilizes the reducing equivalents provided by GSH to suppress the excessive oxidation of polyunsaturated fatty acids. When GSH is depleted or GPX4 is inactivated, the cellular capacity to clear lipid hydroperoxides is significantly compromised, leading to the collapse of the antioxidant defense system [80].

As the primary gateway for iron entry into cells, TFR1 plays a pivotal role in initiating the iron-dependent cascade of ferroptosis. Iron ions acquired via TFR1 fuel the mitochondrial ETC and heme synthesis to support cancer cell survival (Fig. 4). Therefore, targeting TFR1 to disrupt iron acquisition, or exploiting the vulnerability of TFR1-high cancer cells to ferroptosis induction, may serve as a key to overcoming the drug resistance that frequently limits conventional anticancer therapies.

Fig. 4.

Schematic representation of TFR1 in ferroptosis regulation. This schematic illustrates the association between TFR1 and ferroptosis. In cancer cells, the high expression of TFR1 facilitates iron uptake, thereby serving as a key driver of ferroptosis

TFR1 fate regulation

The fate of TFR1 is determined by intricate intracellular sorting systems after completing iron transport into the cell. The majority of TFR1 returns to the plasma membrane via recycling vesicles regulated by Ras-related protein Rab-11 (Rab11) and prepares for the next round of iron transport [81]. In this process, the sorting nexins (SNX) family coordinates the retrograde transport of cargo proteins between endosomes and the Golgi network or plasma membrane [82]. Among them, SNX3 sorts TFR1 into recycling endosomes, accelerating the absorption of Fe³⁺ [83]. A portion of intracellular TFR1 can also be degraded via the lysosomal pathway, a process that depends on the endosomal sorting complex required for transport (ESCRT) complex. Specifically, Beclin 1 facilitates the recruitment of HRS, the core subunit of the ESCRT-0 complex, to the endosomal membrane. This recruitment event initiates cargo sorting, directing ubiquitinated proteins into intraluminal vesicles for subsequent degradation via the lysosomal pathway. However, the downregulation of Beclin 1 in tumors redirects TFR1 from the degradative pathway to the recycling pathway [84].

Apart from Beclin 1, the cell also regulates the degradation of TFR1 through other mechanisms, thereby maintaining iron homeostasis. Under TBK1-mediated phosphorylation, microtubule-associated proteins 1 A/1B light chain 3 C (LC3C) specifically recognizes and binds to early endosomes carrying TFR1, and targets them to the autophagosomal membrane through the ATG9 vesicle transport system, ultimately resulting in TFR1 degradation [85, 86]. Additionally, the epidermal growth factor receptor, which is commonly upregulated in solid tumors, can modulate the subcellular distribution of TFR1 in cancer cells and prevent its entry into the lysosomal degradation pathway, leading to intracellular iron accumulation and ultimately driving tumor progression [87].

In addition to the two sorting pathways mentioned above, Gardner et al. discovered that TFR1 can be packaged into extracellular vesicles through an LC3-mediated secretory autophagy process, facilitated by multiple ESCRT complex components, and is subsequently secreted extracellularly under the regulation of Ras-related protein Rab-27 A [88]. Moreover, Chen et al. found that the guanine nucleotide exchange factor Grab can regulate the exocytosis of TFR1-bearing vesicles by activating Rab8 [89]. The delicate balance formed among these distinct transport pathways plays a critical role in maintaining cellular iron homeostasis, effectively meeting the high demand for iron ions during the rapid proliferation of cancer cells.

In recent years, in-depth elucidation of the molecular mechanisms of TFR1 has led to the discovery of its additional biological functions. Its unique molecular mechanisms and tumor-specific characteristics have made it a hot research topic in cancer therapy [90–92]. By targeting TFR1-mediated iron uptake, it is possible not only to specifically induce ferroptosis in tumor cells but also to potentially overcome resistance to traditional therapies, thereby providing a groundbreaking avenue for developing broad-spectrum antitumor strategies.

Targeting TFR1 for cancer therapy

Targeting TFR1 enhances anticancer efficacy

Disordered iron metabolism is increasingly recognized for its role in cancer initiation and progression. Under physiological conditions, the activation of the proto-oncogene tyrosine-protein kinase (Src) is non-constitutive and depends on the binding of the TF ligand to TFR1 [93]. However, under pathological conditions such as breast cancer, Src escapes this regulatory constraint and forms constitutive persistent binding with TFR1, driving downstream pro-proliferative signals [94]. Meanwhile, cancer cells significantly upregulate TFR1 expression to continuously supply intracellular iron ions, meeting their rapid proliferation demands [95–97]. When intracellular iron accumulation exceeds a critical threshold, ferroptosis is triggered [98]. Based on this mechanism, pharmacological intervention to induce cellular iron overload has emerged as a promising anti-tumor therapeutic strategy. For example, For example, the classic chemotherapeutic agent doxorubicin upregulates TFR1 expression through the HIF-1α signaling pathway, thereby inducing cellular iron overload. The accumulated intracellular Fe²⁺ reacts with doxorubicin-induced H₂O₂ via the Fenton reaction, generating highly reactive hydroxyl radicals. This process subsequently triggers lipid peroxidation, initiates ferroptosis, and ultimately reverses drug resistance in breast cancer cells [99].

To counteract ferroptosis, cancer cells mobilize multiple proteins to cooperatively promote the ubiquitination and degradation of TFR1. For instance, membrane protein complex 2 (EMC2), a core component of the endoplasmic reticulum membrane protein quality control system, maintains cellular homeostasis by regulating membrane protein biogenesis, lipid metabolism, and stress response. Its upregulation in nasopharyngeal carcinoma promotes the degradation of TFR1 and enhances cancer cell resistance to cisplatin [100]. Similarly, in HCC, upregulated CCT3 interacts with ACTN4, inhibiting ferroptosis by impeding TFR1 recycling and ultimately leading to Sorafenib resistance [101]. These findings suggest that targeting the inhibition of TFR1 degradation or directly upregulating TFR1 expression to elevate intracellular iron levels may represent an effective anti-cancer strategy to overcome drug resistance and induce cancer cell death.

TFR1 remodels the tumor microenvironment (TME)

The TME is a dynamic microecological system composed of tumor cells, immune cells, stromal cells, extracellular matrix and the vasculature. The continuous interplay among these components governs tumor initiation, progression, metastasis, and therapeutic response. TFR1 plays multiple critical roles in the immunoregulation of the TME. In HCC, TFR1 on the surface of cancer-associated fibroblasts can bind serum immunoglobulin A, thereby upregulating PD-L1 expression, driving the fibroblasts toward an immunosuppressive phenotype, and ultimately impairing the antitumor activity of CD8⁺ T cells and propelling T cell exhaustion [102]. Sun et al. demonstrated that HCC cells with high TFR1 expression massively deplete iron from the TME, leading to macrophage iron deficiency and consequently promoting their polarization toward a pro-tumorigenic M2 phenotype [103]. Additionally, TFR1-positive cancer cells and neutrophils can augment lactate secretion via the glycolytic pathway, lowering the extracellular pH. The accumulated lactate upregulates arginase-1 expression, thereby suppressing the cytotoxic capacity of CD8⁺ T cells and the phagocytic capability of macrophages [104, 105]. Thus, TFR1 expressed on tumor cells and stromal cells remodels metabolic and immunosuppressive networks, collectively forming a multi-dimensional mechanism that facilitates tumor immune escape (Fig. 5). Regarding targeted intervention, anlotinib, a tyrosine kinase inhibitor, suppresses TFR1 expression in HCC through the VEGFR2/AKT/HIF-1α pathway. This inhibition indirectly leads to upregulated CXCL14 expression, which recruits CD8⁺ T cells for tumor infiltration. The combination of anlotinib with anti-PD-1 antibodies significantly enhances immunotherapeutic efficacy against HCC [106]. This intervention indirectly supports the notion that TFR1 mediates immunosuppression in tumor cells.

Fig. 5.

Schematic diagram depicting intercellular crosstalk within the tumor microenvironment, with emphasis on TFR1-mediated iron transport and immunomodulation among tumor, immune and stromal cells

Current research on targeting TFR1 for cancer therapy reveals two seemingly opposing strategies within the TME. One advocates directly inhibiting TFR1 to suppress cancer cell proliferation, while the other supports upregulating TFR1 to induce ferroptosis, thereby activating T cell-mediated antitumor immune responses [107]. This paradox is not irreconcilable. Given TFR1’s unique endocytic recycling system, precision-targeting strategies should not be confined to a binary choice between “inhibition” and “activation,” but rather aim to achieve precise killing of cancer cells.

TFR1-based novel therapeutic strategies

Aptamer-drug conjugates (ApDCs) targeting TFR1

ApDCs, an emerging class of targeted therapeutics, integrate the precise targeting capability of aptamers with the therapeutic efficacy of drug payloads to enable specific delivery to target cells or tissues [74, 108]. For instance, Wu et al. designed a single-stranded DNA aptamer named XQ-2d that achieves high-affinity binding to TFR1 by recognizing a specific overlapping region with TF on its extracellular domain, mediated by hydrogen bonds and hydrophobic interactions involving 16 key amino acid residues. When loaded with doxorubicin, the resulting complex demonstrates strong potential for targeted therapy against pancreatic cancer [109]. In subsequent testing, the conjugate of XQ-2d with monomethyl auristatin E (MMAE) effectively distinguished uveal melanoma cells from normal human uveal melanocytes and achieved potent targeted inhibition of tumor growth in the mouse xenograft model [110]. Although the XQ-2d-drug conjugate demonstrates significant inhibitory effects on cancer cell proliferation, it is susceptible to nuclease degradation in vivo, which may lead to premature drug release and off-target toxicity. To address this challenge, Yang et al. successfully constructed a targeted delivery system based on the aptamer XQ-2d and mitomycin C using a phosphorothioate modification strategy. This modification significantly enhanced the stability of the aptamer and its binding affinity to TFR1 (with dissociation constant values improving from 39.1 nM to 2.9 nM), while maintaining therapeutic efficacy and substantially reducing off-target toxicity toward non-target cells [111]. Although Aptamer-Drug Conjugates exhibit a relatively short half-life, their small molecular size offers distinct advantages for the treatment of solid tumors (Fig. 6).

Fig. 6.

Schematic representation of aptamer-drug conjugates targeting TFR1 for the treatment of representative cancers

TFR1-targeting antibody drugs

Antibody drugs are a type of highly specific biological macromolecular drugs. Owing to their precise targeting capability and the flexibility for engineering modifications, they have become one of the core strategies in cancer treatment. Among numerous potential tumor targets, TFR1 has gained significant attention as a promising target for antibody-based drug development. In a study using patient-derived xenograft models of natural killer cell leukemia, the humanized anti-TFR1 monoclonal antibody PPMX-T003 blocked the TF-TFR1 axis [112]. Similarly, the use of anti-TFR1 monoclonal antibody RVS10 effectively inhibits the proliferation of human glioblastoma cells [8]. Neiveyans et al. developed a fully human anti-TFR1 monoclonal antibody, H7, which not only depletes intracellular iron but also upregulates TFR1 expression, effectively inhibiting the growth of erythroleukemia and lymphoma (IC50 in the range of 0.1 µg/mL) [113]. In addition to the antibodies mentioned above, antibody drugs targeting TFR1 have demonstrated groundbreaking progress in AIDS-related non-Hodgkin lymphoma. The mouse/human chimeric antibodies ch128.1/IgG1 and ch128.1/IgG3 have demonstrated significant antitumor activity in mouse models by effectively inhibiting the proliferation of malignant B cells [75, 114]. Based on ch128.1/IgG3, the genetically engineered ch128.1-IgG3-Avidin (ch128.1Av) overcomes the limitations of conventional antibodies by achieving precise tumor targeting, efficient drug delivery, and potent therapeutic killing [115–117]. Meanwhile, ch128.1Av overcomes the limitations of HXR9 monotherapy, and their synergistic interaction significantly suppresses malignant B-cell survival [117]. Furthermore, Bratti et al. conjugated a humanized anti-CD71 monoclonal antibody to MMAE via a cleavable linker, to generate INA03. Upon binding to TFR1, the conjugate is rapidly internalized into the lysosomal compartment, where cathepsin B mediates intracellular drug release, effectively reducing tumor burden and prolonging survival in leukemia models. In a TL-Om1 cell line xenograft model, treatment with 1 mg/kg INA03 resulted in 100% survival and complete tumor regression by day 55 [118]. Leveraging the high-affinity binding of anti-TFR1 antibodies to TFR1, conjugating cytotoxic drugs to them, and exploiting the receptor-mediated endocytosis mechanism represent a highly promising therapeutic strategy for tumor eradication (Fig. 7).

Fig. 7.

Schematic representation of anti-TFR1 antibodies for the treatment of representative cancers

TFR1-based nano drug delivery system

In clinical applications, the issue of inefficient drug delivery still needs to be addressed [119]. As a ligand of TFR1, ferritin exploits its pH-dependent reversible assembly and disassembly characteristics, making it a suitable candidate for encapsulating various anticancer drugs and imaging probes [120]. Leveraging its natural high affinity for TFR1 and low immunogenicity, it enhances drug delivery efficiency while avoiding the anemia side effects common in traditional TFR1-targeted therapies. In the treatment of myeloid leukemia, targeted delivery systems based on ferritin nanocages have demonstrated significant advantages. Wang et al. encapsulated trivalent arsenic into human-derived ferritin. This nanodrug significantly enhanced its uptake efficiency by leukemia cells through TFR1-mediated endocytosis, thereby augmenting its cytotoxic effects. In a patient-derived xenograft model of acute lymphoblastic leukemia, 75% of mice in the treatment group remained alive after 6 weeks [121]. Similarly, Wu et al. loaded the first-line clinical drug cytarabine arabinoside into ferritin nanocages. It was demonstrated that this method could be efficiently internalized by leukemia cells and more effectively reduced the leukemia burden compared to free cytarabine arabinoside [5]. In the treatment of solid tumors, ferritin-loaded drugs such as Dox and Cetuximab effectively target TFR1-positive gastric cancer, glioma and breast cancer, significantly inhibiting tumor growth and prolonging survival [122–124]. And the anticancer drug Genz-644,282, delivered using ferritin nanocages, effectively targets both breast cancer and glioma cells with high TFR1 expression while significantly reducing systemic toxicity [73, 125]. Recently, Zhang et al. also developed a ferritin-based hypoxia-targeted nanozyme system that specifically recognizes hypoxic lesion in nasopharyngeal carcinoma and catalyzes the decomposition of H₂O₂ to alleviate hypoxia, thereby enhancing radiosensitivity [72]. Beyond small molecules and chemotherapeutic drugs, ferritin can also facilitate the delivery of small interfering RNA drugs [126]. Although natural ferritin possesses inherent properties such as targeting ability and high biocompatibility, its extremely low loading efficiency for hydrophobic drugs significantly limits its clinical application. To address this, Wang et al. engineered a modified ferritin-based drug carrier, developing a novel drug delivery system named ins-FDC. This system enables highly efficient encapsulation of both hydrophobic camptothecin and hydrophilic epirubicin, which demonstrates significant antitumor efficacy in the treatment of glioma, metastatic liver cancer, and chemotherapy-resistant breast cancer [127]. Furthermore, to expand the loading versatility of ferritin, Palombarini et al. engineered Archaeoglobus fulgidus chimeric ferritin to construct a ternary protein-dendrimer-RNA system which successfully achieved efficient nucleic acid delivery to leukemia cells and induced cell differentiation [128]. Ferritin-based nanocarriers have emerged as a research hotspot in anticancer drug delivery due to their unique hollow structure, excellent biocompatibility, and targeting capabilities (Table 1).

Table 1.

The representative function modules of ferritin-based nanomedicines in cancer therapeutics

Origin of ferritin	Surface modification	Target	Cargo	Cancer type	Anticancer effect	References
Human H ferritin	thiol–maleimide conjugation GSH-cleavable linker Proteolysis‑targeting chimeras	TFR1	Platinum	Esophageal squamous cell carcinoma	Decreased drug resistance Improved anti-tumor activity	[129]
Mouse H ferrin	FAP-α inhibitor	FAP-α TFR1	ATM inhibitor	Colorectal cancer	Alleviated immunosuppression Decreased drug resistance Relieved tumor fibrosis	[130]
Human H ferritin	/	TFR1	5-fluorouracil	Chronic myeloid leukemia	Activation of antitumor immunity	[131]
Human H ferritin	/	TFR1	siRNA_GPX4 Iron ion	Breast cancer	Decreased drug resistance Induced tumor apoptosis Tumor growth inhibition	[126]
Human H ferritin	uPAR targeting peptide MMP-cleavable linker	uPAR TFR1	Zinc Phthalocyanine Tirapazamine	Breast cancer	Tumor growth inhibition	[132]
Human H ferritin	nanobody targeting CD30 and CD5 Granzyme B	CD5 CD30 TFR1	/	T-cell lymphomas Gastric cancer	Induced cancer cell apoptosis Tumor growth inhibition	[133]
Human H ferritin	/	TFR1	Platinum	Nasopharyngeal carcinoma	Cell cycle arrest Decreased drug resistance	[72]
Human H ferritin	/	TFR1	TAPC	Glioma	Anti-metastasis effect Cell cycle arrest Tumor growth inhibition	[134]
Apoferritin	/	TFR1	Tetranuclear Cu(I) complex	Ovarian cancer	Tumor growth inhibition	[135]
Human H ferritin	/	TFR1	Platinum	esophageal squamous cell carcinoma	Induced tumor apoptosis Prolonged survival Tumor growth inhibition	[136]
Human H ferritin	/	TFR1	Doxorubicin	Breast cancer Glioblastoma	Alleviated immunosuppression Prolonged survival Tumor growth inhibition	[137]
Human H ferritin	Trastuzumab	HER2 TFR1	/	Breast cancer	Tumor growth inhibition	[138]
Human H ferritin	/	TFR1	Doxorubicin	Breast cancer Liver cancer	Improved anti-tumor activity Prolonged survival	[139]
Human H ferritin	/	TFR1	Ru(II) polypyridyl complexes	Cervical adenocarcinoma Ovarian adenocarcinoma	Reduced cell viability	[140]
Human H ferritin	RGE-derived peptide	NRP-1 TFR1	STING agonist_SR717	Glioma	Improved anti-tumor activity Prolonged survival	[141]
Human H ferritin	RGD peptide	Integrin α5β3 TFR1	Epirubicin Camptothecin	Glioma Liver cancer	Decreased drug resistance Induced cancer cell death	[142]
Apoferritin	Calcium phosphate shell	TFR1	Arsenic trioxide	Various types of cancer	Tumor growth inhibition	[143]
Human H ferritin	Polyethylene glycol	TFR1	Metal nanoclusters	Colorectal adenocarcinoma	Induced cancer cell death	[144]
Human H ferritin	MMP-cleavable peptide PASE peptide	TFR1	Wide-spectrum topoisomerase I inhibitor_Genz-644,282	Various types of cancer	Tumor growth inhibition	[125]
Human H ferritin	Integrin α2β1 targeting peptide	Integrin α2β1 TFR1	Doxorubicin	Glioblastoma	Induced cancer cell death	[145]
Human H ferritin	tLyP-1 peptide	NRP1 TFR1	Paclitaxel	Breast cancer Liver cancer	Tumor growth inhibition Inhibit proliferation and migration ability of cancer cells	[146]
Human H ferritin	Trastuzumab or Cetuximab	HER2 or EGFR TFR1	/	Brain malignancies	Cell cycle arrest	[147]
Human H ferritin	/	TFR1	Paclitaxel	Glioma	Improved anti-tumor activity Prolonged survival	[148]
Apoferritin	Poly-L-lysine	TFR1	siRNA_EGFR	Various types of cancer	Tumor growth inhibition	[149]
Human H ferritin	Angiopep-2 peptide HREV-107	LRP1 TFR1	Doxorubicin	Glioma	Improved anti-tumor activity	[150]

ATM: ataxia-telangiectasia mutated; EGFR: growth factor receptor I; FAP-α: Fibroblast activation protein-α; HER2: Human Epidermal Growth Factor Receptor 2; Human H ferritin: human-derived ferritin heavy chain; MMP: matrix metalloprotease; Mouse H ferritin: mouse-derived heavy chain ferritin; uPAR: urokinase-type plasminogen activator receptor; PARP: Poly(ADP-ribose) polymerase; PROTAC: Proteolysis-targeting chimeras; TAPC: tetra[4-(amino) piperidin‐1‐yl]‐C6

In addition to the bio-derived protein delivery carriers above, organic nanomaterials also play a significant role in targeted delivery due to their designable chemical structures, excellent biocompatibility, and flexible drug-loading capabilities. Among them, nanoliposomes, as typical organic nanocarriers, enable efficient encapsulation of both hydrophilic and hydrophobic drugs by mimicking the phospholipid bilayer structure. Kang et al. utilized TFR1-targeting antibody RI7217 and muscone to co-modify docetaxel liposomes, enhancing drug delivery to the brain and successfully inhibiting glioma growth [151]. And Wu et al. developed an intelligent liposomal nanosystem that dually targets the metabolic dependencies of pancreatic ductal adenocarcinoma cells and pancreatic stellate cells through the synergistic action of an NF-κB inhibitor and a CD71 aptamer-linked Glut1 siRNA. This strategy significantly inhibited glycolysis by 78.19% and mitochondrial respiration by 88.60%, achieved a tumor penetration depth of 120 μm, and covered over 56.10% of the tumor volume, offering a novel approach to overcome the stromal barrier and metabolic heterogeneity in PDAC [152]. Furthermore, Sun et al. successfully extended the median survival time of glioma-bearing nude mice using TfR-T12-functionalized PEG-PLA/PTX polymeric micelles for paclitaxel delivery (Fig. 8) [153].

Fig. 8.

Schematic representation of nano-drug delivery systems targeting TFR1 for the treatment of representative cancers

In contrast to the bio-derived and organic nano-delivery carriers, inorganic nano-delivery systems demonstrate unique advantages in nanomedicine research by virtue of their precisely tunable physicochemical properties. Bussard et al. utilized the environmentally responsive properties of calcium phosphosilicate nanoparticles to encapsulate the anticancer drug Gemcitabine Monophosphate. Through bioconjugation with an antibody to TFR1, they achieved precise targeting and efficient killing of breast cancer cells [154]. Leveraging the characteristic features of the tumor microenvironment, low pH and high ATP levels, Wu et al. have developed an environmentally responsive DNA nanodevice. This device modulates the HGF/MET signaling pathway, triggering cytoskeletal reorganization and inhibiting cancer cell migration [155]. Additionally, Liu et al. have developed a novel therapeutic approach by synergistic chemo-phototherapy. This system utilizes near-infrared irradiation to achieve intracellular release of paclitaxel in pancreatic cancer cells, reduce desmoplastic stroma, and enhance tumor cell killing efficacy [156].

Degradation of target proteins via TFR1

Many oncogenic driver proteins, such as EGFR and PD-L1, cooperatively drive disease progression through multiple mechanisms. However, conventional small-molecule inhibitors typically target only a single functional domain, making it difficult to achieve comprehensive blockade. Targeted protein degradation technology offers a novel strategy to achieve the elimination of these pathogenic proteins by leveraging two core pathways: the E3 ubiquitin ligase system and the endocytic-lysosomal pathway. Crook et al. developed the CYpHER system, which leverages TFR1 on the cell surface to mediate the internalization and lysosomal degradation of target membrane proteins [157]. Upon completion of target protein delivery, most TFR1 can recycle back to the cell membrane and facilitate secondary drug delivery. Based on this principle, Zhang et al. successfully developed the TransTACs system, which effectively achieves degradation of diverse protein types, including single-pass transmembrane, multi-pass transmembrane, and drug-resistant mutant proteins. By specifically degrading chimeric antigen receptor proteins, the system enables reversible control of T-cell function, establishing a new standard for the safety of cell therapies [14]. Additionally, Xiao et al. created a covalent chimeric peptide-based targeted degradation platform that crosses the blood-brain barrier, reduces PD-L1 expression on tumor cells, dendritic cells, and macrophages, and enhances immune cell-mediated tumor phagocytosis. In an orthotopic brain tumor model, 50% of mice in the v9x treatment group exhibited tumor regression and survived for more than 90 days [158].

Owing to the unique endocytic-recycling characteristics, the targeting of protein degradation via TFR1 demonstrates significant advantages in research (Fig. 9). Regarding the representative drugs for TFR1. Targeting TFR1 offers a promising strategy to markedly improve the targeting efficiency of antitumor drugs. Optimizing ligand design facilitates specific drug enrichment at tumor sites and enhances cellular uptake, thereby supporting the development of more effective and less toxic cancer treatments.

Fig. 9.

Schematic representation of TFR1-based targeted protein degradation for the treatment of representative cancers. POI: protein of interest.

Conclusion

The anticancer therapeutic strategy targeting TFR1 has entered a phase of rapid development, encompassing diverse approaches such as nucleic acid-based drugs, antibody therapeutics, and nano-delivery systems. These methods precisely leverage the biological characteristics of TFR1, including its tumor-specific overexpression and endocytic-recycling mechanism, offering novel solutions to overcome the limitations of conventional therapies and accelerating the clinical translation of cancer-targeted treatments. These strategies not only provide new avenues to reverse drug resistance but also promote the clinical implementation of dual-axis regulatory therapies targeting both iron metabolism and membrane-specific targeting.

In recent years, advances in the functional characterization of TFR1 have revealed roles far beyond its classical function in iron transport, establishing it as a critical target for cancer theranostics. Utilizing TFR1 as a receptor for magnetic core-shell nanoparticles enables early diagnosis of small cell lung cancer [159]. Subsequently, Affatigato et al. engineered a humanized Archaeoglobus fulgidus ferritin to encapsulate superparamagnetic iron oxide nanoparticles forming a complex that achieves selective targeting of breast cancer cells while retaining theranostic functionality [160]. Similarly, Jiang et al. developed an integrated nanoplatform named IRdye800-M-HFn by conjugating an imaging probe and DOX with ferritin, enabling precise early diagnosis and treatment of tumors [139]. These methods overcome the limitation of conventional approaches in diagnosing and treating tumors at their early stages.

Furthermore, a recent study by Hou et al. revealed that unlike its conventional role in iron metabolism, TFR1 can translocate into the nucleus and directly bind to the p53 protein, forming a functional complex that regulates DNA damage repair genes and promotes tumor cell survival [161]. This finding unveils a novel biological function of TFR1, opening new perspectives for developing future TFR1-targeting therapeutic strategies. Upregulating TFR1 surface abundance and reprogramming its expression patterns may enhance intracellular drug accumulation and serve as a key approach to drug sensitization.

Perspectives

The function of TFR1 in tumor biology has extended far beyond canonical iron uptake. Its nuclear translocation, PTMs, and crosstalk with multiple signaling pathways reveal its complex roles in tumor progression and stemness maintenance. At the mechanistic level, the multilayered regulatory network of TFR1 remains largely uncharted. At the post-transcriptional level, the logic of dynamic m⁶A modification, the functional heterogeneity of ceRNA networks, the cross-regulation of IRP activity by oncogenic signals, and the mechanistic contributions of RNA-binding proteins require deeper investigation. At the post-translational level, the crosstalk among different PTMs, the coordinated regulation of TFR1 stability and subcellular localization by key residues, and cancer-type-specific PTM signatures have not been systematically resolved. Regarding biological functions, numerous non-canonical roles of TFR1 remain poorly elucidated. For instance, whether cancer cell-secreted exosome-derived TFR1 is involved in the proliferation and activation of tumor-associated macrophages.

In terms of targeted therapy, although anti-TFR1 antibodies, nanocarriers, and novel degraders have shown potential, off-target toxicity in normal tissues and primary and acquired resistance driven by tumor heterogeneity remain core obstacles to clinical translation. The long-term effects of most targeting strategies on normal proliferating tissues with high TFR1 expression and on systemic iron homeostasis have not been systematically evaluated. Beyond known defects in degradation and endocytosis, resistance mechanisms such as the activation of compensatory iron uptake pathways also await clarification. Most current strategies remain at the preclinical stage, and their pharmacokinetics, pharmacodynamics, and optimal combination regimens have yet to be validated. Furthermore, it is essential to develop tissue-specific, microenvironment-responsive delivery vehicles and novel protein degradation technologies.

In clinical translation, early-phase clinical trials should be conducted by integrating individual patient characteristics and prioritizing cancer types with high TFR1 expression and resistance to existing therapies, such as acute leukemia, glioma, and triple-negative breast cancer. Meanwhile, the long-term safety of targeted therapy should be systematically monitored, and corresponding toxicity intervention strategies should be developed. In summary, in-depth dissection of the complex regulatory network and functional heterogeneity of TFR1, combined with innovative translation through multimodal technological approaches, will lay a critical foundation for advancing TFR1 research from basic science toward precision therapy.

Abbreviations

3'UTR

3’ untranslated region

Ac

Acetylation

ADC

Antibody-drug conjugates

AKT

Serine/threonine kinase 1

ALKBH5

Alkylation repair homolog protein 5

AP2

Adaptor protein complex 2

ApDC

Aptamer-drug conjugate

Asn

Asparagine

ATF3

Activating transcription factor 3

ATP1A1

Sodium/potassium-transporting ATPase subunit alpha-1

AXIN2

Axis inhibition protein 2

CAF cell

Cancer-associated fibroblasts cell

CD36

Cluster of differentiation 36

CEBPB

CCAAT/enhancer-binding protein beta

ch128.1Av

Ch128.1-IgG3-Avidin

circRNA

Circular RNA

c-Myc

Avian myelocytomatosis virus oncogene cellular homolog

COPI

Coat protein complex I

COPII

Coat protein complex II

CXCL14

C-X-C motif chemokine ligand 14

CYLD

Cylindromatosis

DMT1

Divalent metal transporter 1

EBV

Epstein-Barr Virus

EEA1

Early endosome antigen 1

EGFR

Growth factor receptor I

EIF4A3

Eukaryotic translation initiation factor 4A3

ETC

Electron transport chain

FBXL5

F-box and leucine-rich repeat protein 5

Fe²⁺

Ferrous iron

Fe³⁺

ferric iron

FosL1

fos-related antigen 1

FPN1

Ferroportin 1

FTH

Ferritin heavy chain

FTL

Ferritin light chain

FTO

Fat mass and obesity associated

Grab

Guanine nucleotide exchange factor for Rab

H₂O₂

Hydrogen peroxide

HCC

Hepatocellular carcinoma

HDAC9

Histone deacetylase 9

HIF-1

Hypoxia-inducible factor 1

HIV

Human immunodeficiency virus

HRE

Hypoxia response element

HUWE1

HECT, UBA and WWE domain-containing protein 1

IgA

Immunoglobulin A

IGF2BP2

Insulin-like growth factor 2 mRNA‐binding protein 2

IgG1

Immunoglobulin G1

IgG3

Immunoglobulin G3

INFγ

Interferon-gamma

IRE

Iron-responsive element

IRP1

Iron-regulatory Protein 1

IRP2

Iron-regulatory Protein 2

JNK

C-Jun N-terminal kinase

Lac

Lactylation

LAMP1

Lysosomal-associated membrane protein 1

LATS1

Large tumor suppressor kinase 1

LC3C

Microtubule-associated proteins 1 A/1B light chain 3 C

LC3-II

Microtubule-associated protein 1 A/1B-light chain 3-II

Lnc RIM

lncRNA related to iron metabolism

LncRNA

Long non-coding RNA

LPO

Lipid peroxidation

LSD1

Lysine-specific demethylase 1

m⁶A

N6-methyladenosine

MARCH8

Membrane associated ring-CH-type finger 8

MDA

Malondialdehyde

METTL3

Methyltransferase-like 3

METTL4

Methyltransferase-like protein 4

MFN2

Mitofusin 2

MMAE

Monomethyl auristatin E

MTCH2

Mitochondrial carrier homolog 2

m-TOR

Mechanistic target of rapamycin

NF2

Merlin

NF-κB

Nuclear factor kappa B

NUF2

Ndc80 kinetochore complex component

O-GlcNac

O-GlcNAcylation

ox-LDL

Oxidized low-density lipoprotein

P

Phosphorylation

p38

p38 mitogen-activated protein kinase

p53

Cellular tumor antigen p53

p62

Sequestosome 1

PD-1

Programmed cell death protein 1

PKC

Protein pinase C

POI

Protein of interest

PTM

Post-translational modifications

RAB5

RAS-associated binding protein 5

RAB7

RAS-associated binding protein 7

RAB8

RAS-associated binding protein 8

RAB11

RAS-associated binding protein 11

ROS

Reactive oxygen species

scFV-Fc

Single-chain fragment variable-fragment crystallizable

siRNA

Small interfering RNA

SNX3

Sorting nexin 3

SP1

Specificity protein 1

SRC

Sarcoma proto-oncogene

STAT5

Signal transducer and activator of transcription 5

STEAP3

Six-transmembrane epithelial antigen of prostate 3

TAZ

Tafazzin

TCA Cycle

Tricarboxylic acid cycle

TEAD4

TEA domain transcription factor 4

TF

Transferrin

TFEB

Transcription factor EB

TFR1

Transferrin Receptor 1

TGFBR

Transforming growth factor beta receptor

TGF-β

Transforming Growth Factor-beta

TIGIT

T-cell immunoreceptor with Ig and ITIM domains

TIM-3

T-cell immunoglobulin and mucin-containing-domain-3

TME

Tumor Microenvironment

TNF-α

Tumor necrosis factor alpha

TNKS

Tankyrase

Treg

Tegulatory T

TRIM33

Tripartite Motif Containing 33

Ub

Ubiquitination

VEGFR2

Vascular endothelial growth factor receptor 2

XPC

Xeroderma pigmentosum, complementation group C

YAP

Yes-Associated Protein

YTHDF1

YTH domain-containing family protein 1

YTHDF3

YTH domain-containing family protein 3

Author contributions

FXF: Writing - original draft, Conceptualization; YF: Writing - review and editing, Visualization; ZDW: Data curation, Writing - review and editing; YPQ: Visualization, Data curation; HQ: Writing - original draft, Conceptualization, Writing - review and editing; KY: Writing - review and editing, Funding acquisition, Supervision.

Funding

This work was supported by the National Key Research and Development Program of China (No. 2024YFA1108701), the National Natural Science Foundation of China (Nos. 82471107, 82501321 and 31970930), the Hubei Natural Science Foundation (Nos. 2025AFB042, 2020CFA069 and 2018CFB434), the Neuroscience Team Development Project of Wuhan University of Science and Technology (Nos. 1180002 and 1180030) and the Graduate Innovation and Entrepreneurship Foundation of Wuhan University of Science and Technology (No. JCX2024034).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.