Editorial: The potential of transferrin as a drug target and delivery molecule

Patricia Carrilho ¹ Sidharth Chopra ² Mallikarjuna Rao Pichika ³ Robert Fleming ⁴ Nermi Parrow ^4*

• ¹ Hospital Prof. Doutor Fernando Fonseca, EPE, Amadora, Portugal
• ² CSIR-Central Drug research institute, Lucknow, India
• ³ Newcastle University Medicine Malaysia, Johor, Johor, Malaysia
• ⁴ School of Medicine, Saint Louis University, St. Louis, United States

functions. It has two homologous lobes, N and C, each of which can bind one iron molecule. Clefts in these lobes close upon binding iron (Luck and Mason, 2012), resulting in a conformational shift that alters the affinity for transferrin receptors and may have additional consequences for protein-protein interactions. The ability of each lobe to independently bind an iron atom results in four circulating species of Tf: apoTf, monoferric N, monoferric C and holoTf. The monoferric forms of transferrin influence erythropoietin sensitivity and iron homeostasis (Parrow et al., 2019). Thus, targeting them may have therapeutic potential in diseases characterized by erythropoietin resistance or dysfunctional hepcidin levels.Transferrin has two receptors, transferrin receptor 1 (TFR1) and transferrin receptor 2 (TFR2). TFR1 is ubiquitously expressed, including in brain endothelium (Roberts et al., 1993), and primarily serves to deliver iron from transferrin to cells. At serum pH, iron loaded Tf binds TFR1 with high affinity and the complex undergoes endocytosis. A decrease in endosomal pH promotes the release of iron from Tf and the apo-Tf-TfR1 complex is recycled to the cell surface where apoTf is released (Steere et al., 2012). TFR1 is upregulated in highly proliferative cells (Zhang et al., 2024) and in response to iron deficiency (Tong et al., 2002, O'Donnell et al., 2006, Meyron-Holtz et al., 2004).TFR2 is thought to primarily serve as a signaling receptor. In mice (Fleming et al., 2002) and humans (Camaschella et al., 2000), loss of TFR2 results in hereditary hemochromatosis, a disorder characterized by excessive iron absorption secondary to inappropriately low hepcidin levels This collection focuses on Tf as a therapeutic target and a drug delivery system.Li et al present a review of the potential therapeutic applications of Tf (Frontiers | Pathophysiological aspects of transferrin-A potential nano-based drug delivery signaling molecule in therapeutic target for varied diseases). They provide an overview of the use of TF as a therapeutic agent in various clinical conditions. One of these is transferrin replacement therapy in the rare transferrin deficiency disease, atransferrinemia. Another is the use of transferrin therapies, such as the administration of ApoTf, to neutralize free iron in ischemia reperfusion injury models. This review also covers an array of studies where chemotherapeutics or imaging agents are delivered via transferrin-conjugated moieties or are otherwise directed to TfR1 by antibody or peptide. These approaches leverage the upregulation of TfR1 that characterizes proliferating tumor cells.He et al also present studies investigating transferrin-conjugated therapies or TfR1 targeting in the context of reviewing the potential for natural products to alleviate chemotherapy-related cognitive impairment (Frontiers | Natural products for the treatment of chemotherapy-related cognitive impairment and prospects of nose-to-brain drug delivery). One such study indicates that targeting nanocarrier wrapped ginsenoside RG1 (an active constituent of ginseng) to TfR1 increased penetration of the blood brain barrier and decreased brain infarct volume in a cerebral ischemia model (Shen et al., 2019). He and colleagues also propose nose-to-brain delivery as a mechanism to bypass the blood brain 41 barrier. Proof of principle is provided by at least one study that generated and transferrin-42 conjugated chitosan nanoparticles (Gabold et al., 2023). Nanoparticles with the highest surface 43 expression of transferrin had the highest uptake in a human nasal epithelial cell line and transferrin-44 conjugated nanoparticles passed more quickly through an epithelial layer to glioblastoma cells in co-45 culture model systems. 46In a specific study of transferrin as delivery system, Alrouji and colleagues present a primary 47 investigation of the binding mechanism of capsaicin with human transferrin (Frontiers | Evaluation of 48 binding mechanism of dietary phytochemical, capsaicin, with human transferrin: targeting 49 neurodegenerative diseases therapeutics). Capsaicin is the primary component of chili pepper. Recent 50 studies suggest dietary capsaicin may have neuroprotective properties, with specific therapeutic 51 potential for Alzheimer's disease (Wang et al., 2020, Xu et al., 2017). Transferrin provides a potential 52 means to deliver capsaicin across the blood brain barrier via TfR1. Using a combination of approaches, 53their studies indicate that capsaicin binds transferrin in the iron binding pocket without significant 54 structural alterations. They report a binding constant of 3.99 x 10 6 M -1 , indicating that transferrin has a 55 considerably lower affinity for capsaicin compared to Fe 3+ (Aisen et al., 1978). In vivo studies comparing 56 the efficacy of transferrin-mediated capsaicin delivery to dietary capsaicin in mouse models of disease 57 will be useful in evaluating the feasibility of this approach. 58 59 Ren and colleagues present an umbrella review of meta-analyses of the effects of the prolyl hydroxylase 60 inhibitors (PHI) on anemia in chronic kidney disease (Frontiers | Efficacy and safety of hypoxia-inducible 61 factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of 62 meta-analyses). This class of drugs inhibits the oxygen-dependent prolyl hydroxylases responsible for 63 degradation of hypoxia inducible factor (HIF) (Haase, 2021). HIF controls the myriad responses to hypoxia 64 (Semenza, 2012) and transferrin itself is upregulated in response to hypoxia (Li et al., 2022). Their meta-65 analysis confirms an increase of ~ 1g of hemoglobin per deciliter in studies of PHIs. As expected, the 66 increase is more pronounced compared to placebo than to erythropoiesis stimulating agents (ESAs).Treatment with PHIs decreases levels of the hepatic iron regulatory hormone hepcidin, also 68 demonstrating a stronger effect compared to placebo than to ESAs. Surprisingly, 7 of 11 studies analyzed 69 did not show a significant difference in serum iron concentration compared to ESA or placebo. There 70 was, however, evidence of increased total iron binding capacity, a surrogate measure of transferrin, and 71 transferrin level itself. A corresponding decrease in transferrin saturation was also observed. Based on 72 the demonstrated capacity of lobe occupancy of transferrin to influence erythropoietin responsiveness 73 and iron homeostasis, it is tempting to speculate that the upregulation of transferrin by the prolyl 74 hydroxylase inhibitors may have previously unrecognized effects on the distribution of iron bound 75 transferrin species that contribute to the efficacy of these therapeutics in the anemia of chronic kidney 76In total, this collection provides exciting evidence that transferrin has therapeutic utility in a variety of 78 diseases. Additionally, targeting TfR1 may provide specific mechanisms for delivering chemotherapeutics 79 and imaging modalities to rapidly proliferating cells, as well as bypassing the blood brain barrier. We 80 look forward to the continued development of drugs based on transferrin.