Transferrin Receptor Research Articles

Ferritin Outperforms Other Biomarkers in Predicting Bone Marrow Iron Stores in Hematological Patients.

Although iron deficiency anemia is common, interpreting iron laboratory test results can be challenging in patients with comorbidities. We aimed to study the accuracy of common iron biomarkers compared with bone marrow iron staining in a large retrospective dataset of hematological patients. We collected from 6610 patients (median age 66 years) results of iron staining, with their concurrent ferritin, transferrin saturation, soluble transferrin receptor, transferrin, hemoglobin, and mean red blood cell volume results from Helsinki University Hospital electronic health records. In receiver operating characteristics (ROC) analysis, ferritin had the highest area under curve (AUC) with 88% (95% CI 86-90%) for females and 89% (87-91%) for males in predicting reduced bone marrow iron. Using a ferritin cut-off of 30 µg/L resulted in high specificity rates of 97% in females and 99% in males. However, sensitivity rates were only 54% and 35%, respectively. Other studied biomarkers had inferior AUCs. Multivariate logistic regression models did not significantly perform better in prediction compared to ferritin alone. With 50% pre-probability for reduced iron stores, a ferritin of 30 µg/L (females) and 51 µg/L (males) had 95% positive predictive value for reduced iron stores. A 95% negative predictive value was achieved at 1750 µg/L (females) and 4967 µg/L (males). In our large population study, ferritin was the best single biomarker for iron deficiency in secondary care. Adding other blood tests in a multivariate model did not improve performance. However, in these hematological patients, even a high ferritin did not rule out iron deficiency with 95% certainty.

Association of iron deficiency and anemia with obesity among children: A systematic review and meta-analysis.

Obesity is a potential risk factor for anemia in children. This systematic review (SR) was undertaken to estimate the association of obesity with iron deficiency (ID) and ID anemia (IDA), in children. A systematic literature search for observational studies was done in PubMed, EMBASE, Scopus, and the Cochrane library, with additional hand-searching. Two reviewers independently screened the search output, included eligible studies, extracted data, and assessed study quality using the National Institutes of Health tool. The main outcomes were association of obesity with anemia (IDA), and ID. Secondary outcomes were hemoglobin level, serum iron, ferritin, transferrin receptor saturation, and hepcidin. Meta-analysis was done using a random-effects model. Comparisons were expressed through pooled OR with 95% CI. Forty-two studies comprising one cohort, 29 cross-sectional, and 12 case-control studies comparing 16,633 children living with obesity and 32,573 children without obesity were included. The pooled OR (95% CI) for ID was 1.64 (1.22, 2.21), 16 studies, 20,949 children; and 0.78 (0.43, 1.43), 17 studies, 40,022 children, for IDA. The pooled prevalence of ID was 20.07% (14.98, 25.16) among children living with obesity (16 studies, 3147 children), compared to 16.1% (11.82, 20.38) in children without obesity. Children living with obesity had significantly lower levels of hemoglobin, iron, % transferrin saturation, and higher levels of ferritin and hepcidin than children without obesity. There is a significant association between iron deficiency and obesity in children.

Multi-pathway oxidative stress amplification via controllably targeted nanomaterials for photoimmunotherapy of tumors

Photoimmunotherapy, which combines phototherapy with immunotherapy, exhibits significantly improved therapeutic effects compared with mono-treatment regimens. However, its use is associated with drawbacks, such as insufficient reactive oxygen species (ROS) production and uneven photosensitizer distribution. To address these issues, we developed a controllable, targeted nanosystem that enhances oxidative stress through multiple pathways, achieving synergistic photothermal, photodynamic, and immunotherapy effects for tumor treatment. These nanoparticles (D/I@HST NPs) accurately target overexpressed transferrin receptors (TfRs) on the surface of tumor cells through surface-modified transferrin (Tf). After endocytosis, D/I@HST NPs generate ROS under 808-nm laser irradiation, breaking the ROS-responsive crosslinking agent and increasing drug release and utilization. Tf also carries Fe3+, which is reduced to Fe2+ by iron reductase in the acidic tumor microenvironment (TME). Consequently, the endoperoxide bridge structure in dihydroartemisinin is cleaved, causing additional ROS generation. Furthermore, the released IR-780 exerts both photodynamic and photothermal effects, enhancing tumor cell death. This multi-pathway oxidative stress amplification and photothermal effect can trigger immunogenic cell death in tumors, promoting the release of relevant antigens and damage-associated molecular patterns, thereby increasing dendritic cell maturation and sensitivity of tumor cells to immunotherapy. Mature dendritic cells transmit signals to T cells, increasing T cells infiltration and activation, facilitating tumor growth inhibition and the suppression of lung metastasis. Furthermore, the myeloid-derived suppressor cells in the tumor decreases significantly after treatment. In summary, this multi-pathway oxidative stress-amplified targeted nanosystem effectively inhibits tumors, reverses the immunosuppressive tumor microenvironment, and provides new insights into tumor immunotherapy combined with phototherapy.

Hypoxia-tropic delivery of nanozymes targeting transferrin receptor 1 for nasopharyngeal carcinoma radiotherapy sensitization

Nasopharyngeal carcinoma (NPC), a malignancy highly prevalent in East and Southeast Asia, is primarily treated with radiotherapy (RT). However, hypoxia-induced radioresistance presents a significant challenge. Nanozymes, nanomaterials with catalase-like activity, have emerged as a promising strategy for radiosensitization by converting elevated hydrogen peroxide in the tumor microenvironment into oxygen. Despite their potential, effectively targeting hypoxic lesions has been difficult. Here, we identify transferrin receptor 1 (TfR1) as an upregulated target in NPC, with its expression levels positively correlated with hypoxia. Human heavy-chain ferritin, a specific ligand of TfR1, selectively recognizes hypoxic NPC lesions in preclinical models. Based on these findings, we design a hypoxia-targeted nanozyme by loading platinum nanoparticles into ferritin. This nanozyme exhibits enhanced catalase-like activity and effectively alleviates tumor hypoxia in NPC xenografts. When combined with RT, a single injection of the nanozyme significantly inhibits tumor growth and prolongs mouse survival, outperforming sodium glycididazole, a clinically used radiosensitizer. In summary, our findings highlight TfR1 as an accessible cell surface target in hypoxic NPC lesions. The nanozyme targeting TfR1 holds promise for enhancing the therapeutic effectiveness of RT in NPC through an in situ oxygen-generation mechanism.

Transferrin Saturation, Serum Iron, and Ferritin in Heart Failure: Prognostic Significance and Proteomic Associations.

Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID. We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism. Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76-0.93]; P=0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79-0.96]; P=0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83-0.95]; P=0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, -0.455; P<0.0001) and CRP (C-reactive protein; β, -0.355; P<0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID. Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.

Transferrin Receptor 2 in Canine Testicular Tumors: An Emerging Key Role in Seminomas.

Transferrin Receptor 2 (TfR2) is a homolog of Transferrin Receptor 1 (TfR1), involved in regulating intra and extracellular iron levels. Altered iron pathways have been associated with cancer onset and progression; however, their role in canine tumors remains poorly explored. This study investigated TfR2 immunohistochemical expression in non-neoplastic canine testis for the first time and in the most common types of canine testicular tumors: intratubular seminomas (ITSEMs), diffuse seminomas (DSEMs), Leydig cell tumors (LCTs), and Sertoli cell tumors (SCTs). Immunohistochemical analysis revealed a differential pattern of TfR2 expression according to tumor type, with high expression observed in ITSEMs and DSEMs, occasional expression in LCTs, and absence in SCTs. These results suggest that TfR2 may play a relevant role in canine seminoma development. Furthermore, the specific expression of TfR2 in seminomas highlights its potential as a therapeutic target, where its role in iron regulation and possible compensatory mechanisms warrant further investigation.

FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models

BackgroundWe developed the FORCETM platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression.MethodsMultiple surrogate conjugates were generated to characterize the FORCE platform. DYNE-101 is the conjugate designed to target DMPK and correct spliceopathy for the treatment of DM1. HSALR and TfR1hu/mu;DMSXLTg/Tg mice were used as models of myotonic dystrophy, the latter expresses human TfR1 and a human DMPK RNA with >1,000 CUG repeats. Cynomolgus monkeys were used to determine translatability of DYNE-101 pharmacology to higher species.ResultsIn HSALR mice, a surrogate FORCE conjugate achieves durable correction of spliceopathy and improves myotonia to a greater extent than unconjugated ASO. In patient-derived myoblasts, DYNE-101 reduces DMPK RNA and nuclear foci, consequently improving spliceopathy. In TfR1hu/mu;DMSXLTg/Tg mice, DYNE-101 reduces mutant DMPK RNA in muscle, thereby correcting splicing. Reduction of DMPK foci in cardiomyocyte nuclei accompanies these effects. Low monthly dosing of DYNE-101 in TfR1hu/mu;DMSXLWT/Tg mice or cynomolgus monkeys leads to a profound reduction of DMPK expression in muscle.ConclusionsThese data validate FORCE as a drug delivery platform and support the notion that DM1 may be treatable with low and infrequent dosing of DYNE-101.

Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins.

Targeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis-related proteins. Aptamer-based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off-target effects due to the non-covalent interaction with target proteins. We here report the first design of a covalent aptamer-based autophagosome-tethering chimera (CApTEC) for the enhanced autophagic degradation of cell-surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL). This strategy relies on the site-specific incorporation of sulfonyl fluoride groups onto aptamers to enable the cross-linking with target proteins, coupled with the conjugation of an LC3 ligand to hijack the autophagy-lysosomal pathway for targeted protein degradation. The chemically engineered CApTECs exhibit enhanced on-target retention and improved structural stability. Our results also demonstrate that CApTECs achieve remarkably enhanced and prolonged degradation of membrane proteins compared to the non-covalent designs. Furthermore, the CApTEC targeting TfR1 is combined with 5-fluorouracil (5-FU) for synergistic tumor therapy in a mouse model, leading to substantial suppression of tumor growth. Our strategy may provide deep insights into the LC3-mdiated autophagic degradation, affording a modular and effective strategy for membrane protein degradation and precise therapeutic applications.

Ferritin nanoparticles: new strategies for the diagnosis and treatment of central nervous system diseases.

Ferritin nanocarriers, which can penetrate the blood-brain barrier (BBB), have gained significant research interest for the diagnosis and treatment of central nervous system (CNS) diseases, including gliomas, Alzheimer's disease, and brain metastases. In recent years, ferritin has been proved as a candidate to cross the BBB using receptor-mediated transcytosis (RMT) mechanism through transferrin receptor 1 (TfR1) which is overexpressed in the cells of the BBB. Various types of cargo molecules, including therapeutics, imaging agents, nucleic acids, and metal nanoparticles, have been incorporated into ferritin nanocages for the diagnosis and treatment of CNS diseases. In particular, low immunogenicity of ferritin implies safety for its usage in clinical practices, and high biocompatibility add to the perspectives of its applications. Furthermore, contemporary strides in molecular biology have enabled some alteration in the configuration of the ferritin outer layers and surface characters so as to enhance the drug encapsulation capacity and conjugation affinity. Such modifications not only enhance the property of ferritin in crossing the BBB, but also enhance its efficacy when applied to CNS diseases. In summary, ferritin, as a drug delivery system, shows great potential for the treatment and diagnosis of central nervous system diseases.

Iron metabolism in a mouse model of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains the most prevalent type of primary liver cancer worldwide. p53 is one of the most frequently mutated tumor-suppressor genes in HCC and its deficiency in hepatocytes triggers tumor formation in mice. To investigate iron metabolism during liver carcinogenesis, we employed a model of chronic carbon tetrachloride injections in liver-specific p53-deficient mice to induce liver fibrosis, cirrhosis and subsequent carcinogenesis. A transcriptome analysis of liver carcinoma was employed to identify p53-dependent gene expression signatures with subsequent in-depth analysis of iron metabolic parameters being conducted locally within liver cancers and at systemic levels. We show that all mutant mice developed liver cancer by 36-weeks of age in contrast to 3.4% tumors identified in control mice. All liver cancers with a p53-deficient background exhibited a local iron-poor phenotype with a “high transferrin receptor 1 (Tfr1) and low hepcidin (Hamp)” signature. At systemic levels, iron deficiency was restricted to female mice. Additionally, liver tumorigenesis correlated with selective deficits of selenium, zinc and manganese. Our data show that iron deficiency is a prevalent phenomenon in p53-deficient liver cancers, which is associated with alterations in Hamp and Tfr1 and a poor prognosis in mice and patients.

Micronutrient status and risk of Mycobacterium tuberculosis infection in Indonesian tuberculosis case contacts.

Certain micronutrient levels have been associated with the risk of developing TB disease. We explored the possible association of selected at-risk micronutrient levels with the development of Mycobacterium tuberculosis (M.tb) infection. This cohort study in Bandung, Indonesia, followed Interferon Gamma Release Assay (IGRA) negative TB case contacts with a repeat IGRA test at 3 mo. At baseline, blood was analysed for haemoglobin, 25-hydroxyvitamin D, retinol-binding protein, C-reactive protein, alpha-1-acid glycoprotein, serum transferrin receptor (sTfR), ferritin, zinc and selenium. Total body iron was calculated using ferritin and sTfR status. Associations between case contact micronutrient concentration and IGRA conversion were estimated using Poisson regression. Of 430 contacts, 115 (27%) underwent IGRA conversion. Ferritin concentration (adjusted for inflammation) was positively associated with risk of IGRA conversion (incidence rate ratio [IRR] for ferritin=1.17; 95% CI 1.01 to 1.35; p=0.03), but other select micronutrients were not. This association held for ferritin in the final multivariable model (IRR=1.27; 95% CI 1.09 to 1.47; p=0.002). The risk of developing M.tb infection, as defined by IGRA conversion, is associated with increasing ferritin. Interventions in TB case contacts to temporarily reduce iron levels, including considering withholding any iron supplementation, may be worthy of evaluation.

CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis.

This study aims to investigate the role and mechanism of p-hydroxyl cinnamaldehyde (CMSP) in triggering ferroptosis of small cell lung cancer (SCLC) cells. The impact of CMSP on ferroptosis in H1688 and SW1271 cells was assessed through cell experiments and biological information analysis. Moreover, the expression of heme oxygenase 1 (HMOX1) in SCLC tissue was examined. Following CMSP treatment, a concentration-dependent increase in cell death was observed, and differentially expressed genes were found to be associated with ferroptosis. CMSP notably facilitated ferroptosis events, such as elevated levels of reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), transferrin receptor 1 (TFR1), divalent metal transporter 1 (DMT1), and decreased levels of glutathione (GSH), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Furthermore, CMSP promoted mitochondrial dysfunction, manifested as reduced mitochondrial volume, increased membrane density, elevated mitochondrial ROS, and decreased mitochondrial membrane potential. Consistently, the mitochondrial-targeted antioxidant Mito-TEMPO reversed CMSP-induced ferroptosis. Expression of the HMOX1 gene was markedly increased under CMSP treatment, while lower expression was observed in cancer tissue compared to adjacent tissue. CMSP triggers mitochondrial dysfunction via HMOX1 activation, leading to ferroptosis in SCLC cells, underscoring its potential as a therapeutic agent for SCLC.

H3K14la drives endothelial dysfunction in sepsis-induced ARDS by promoting SLC40A1/transferrin-mediated ferroptosis.

Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Integrative lactylome and proteome analyses were performed to identify the global lactylome profile in the lung tissues of septic mice. Cut&Tag analysis was used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Septic mice presented elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. For the first time, we reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of the glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.

Local erythropoiesis directs oxygen availability in bone fracture repair.

Bone fracture ruptures blood vessels and disrupts the bone marrow, the site of new red blood cell production (erythropoiesis). Current dogma holds that bone fracture causes severe hypoxia at the fracture site, due to vascular rupture, and that this hypoxia must be overcome for regeneration. Here, we show that the early fracture site is not hypoxic, but instead exhibits high oxygen tension (> 55 mmHg, or 8%), similar to the red blood cell reservoir, the spleen. This elevated oxygen stems not from angiogenesis but from activated erythropoiesis in the adjacent bone marrow. Fracture-activated erythroid progenitor cells concentrate oxygen through haemoglobin formation. Blocking transferrin receptor 1 (CD71)-mediated iron uptake prevents oxygen binding by these cells, induces fracture site hypoxia, and enhances bone repair through increased angiogenesis and osteogenesis. These findings upend our current understanding of the early phase of bone fracture repair, provide a mechanism for high oxygen tension in the bone marrow after injury, and reveal an unexpected and targetable role of erythroid progenitors in fracture repair.

Berberine ameliorates seizure activity and cardiac dysfunction in pentylenetetrazol-kindling seizures in rats: Modulation of sigma1 receptor, Akt/eNOS signaling, and ferroptosis.

Seizures can lead to cardiac dysfunction. Multiple pathways contribute to this phenomenon, of which the chaperone sigma-1 receptor (S1R) signaling represents a promising nexus between the abnormalities seen in both epilepsy and ensuing cardiac complications. The study explored the potential of Berberine (BER), a promising S1R agonist, in treating epilepsy and associated cardiac abnormalities in a pentylenetetrazol (PTZ) kindling rat model of epilepsy. Male Wistar albino rats received PTZ (35 mg/kg) every other day alone, with BER, with phenytoin (PHT), with both BER and PHT and with both BER and an S1R blocker (NE-100) over 27 days. BER decreased seizure severity and improved hemodynamic parameters. Histopathological abnormalities were more pronounced in the PTZ, and blocker group than in other groups, in heart tissue. In cardiac tissue, BER enhanced the AKT/eNOS signaling pathway and mitigated ferroptosis by boosting the cystine/glutamate transporter/ Glutathione/ Glutathione Peroxidase 4 (XCT/GSH/GPX4) system and ferritin heavy chain-1 (FTH-1) expression, while reducing iron and Transferrin receptor protein 1 (TFR1) levels. Such effects were largely negated by NE-100 pretreatment. In conclusion, BER shows protective effects on cardiac dysfunction induced by the PTZ kindling model by acting as an S1R agonist and influencing the AKT/eNOS signaling pathway and ferroptosis.

How prevalent are lactoferrin receptors in Gram-negative bacteria?

Surface receptors in Gram-negative bacteria that bind and extract iron from the host glycoproteins transferrin (Tf) or lactoferrin (Lf) was discovered 35 years ago in pathogenic Neisseria species and subsequently was discovered in other pathogens of humans and food production animals. These bacterial species reside exclusively on the mucosal surfaces of the respiratory or genitourinary tract of their mammalian host and rely on their host specific Tf and Lf receptors to acquire iron for survival. Since the specificity of the bacterial Tf receptors was shown to be due to selective pressures on the host Tf, their presence in bacteria that reside in both mammals and birds indicates that they arose over 320 million years ago. Once Lf arose in mammals due to a gene duplication event, Lf receptors subsequently arose from Tf receptors. The focus on pathogens for discovery of these receptors has led to a limited understanding of how prevalent the Tf and Lf receptors are in commensal species and raises the question whether they are present in additional bacterial lineages. Since the Lf receptor provides a secondary iron acquisition system plus can provide protection from cationic peptides its presence varies in bacterial lineages.

Transferrin receptor uptakes iron from tumor-associated neutrophils to regulate invasion patterns of OSCC

BackgroundTransferrin receptor (TFRC) uptakes iron-loaded transferrin (TF) to acquire iron and regulates tumor development. Nonetheless, the clinical values and the precise functions of TF-TFRC axis in the development of oral squamous cell carcinoma (OSCC) were still undiscovered, especially the impacts of their regional heterogeneous expression.MethodsImmunohistochemistry (IHC) was used to analyze the expression of TFRC in 106 OSCC patients. Then the prognostic value of TFRC was compared between high and low worst pattern of invasion (WPOI) patients. OSCC cells with low or high expression of TFRC were constructed, and functional experiments were performed to elucidate the effects of TFRC on the migration and proliferation of OSCC cells. Multi-immunofluorescence was applied to stain TF and tumor-associated neutrophils (TANs). The stimulating effects of TF were compared between normal and high TFRC cells in vitro and across different OSCC patients’ subgroups in our sample bank and TCGA database.ResultsHigher TFRC was expressed at invasive tumor front (ITF) in OSCC and correlated with WPOI. Only at ITF in patients with WPOI 4–5, TFRC was a prognostic factor. High TFRC promoted migration and proliferation of cancer cells. Additionally, TANs secreted TF outside. Exogenous TF promoted migration and proliferation of cells with high expression of TFRC. Compared to the TANslowTFRClow OSCC patients, TANshighTFRChigh OSCC patients had poorer clinical outcomes.ConclusionsHigher expression of TFRC at ITF and TANs-TF-TFRC axis promoted OSCC invasion at ITF by facilitating cell migration and proliferation, which may result from increased cellular iron uptake through regulating iron metabolism.

Mechanisms Underlying Iron Deficiency-Induced Cardiac Disorders: Implications for Treatment.

Two billion people worldwide suffer from anemia, which can lead to the onset of cardiac disorders; nevertheless, the precise mechanisms remain unclear. There are at least three distinct mechanisms by which iron deficiency (ID) contributes to the development of cardiac disorders. First, ID increases concentrations of intact fibroblast growth factor-23 (iFGF-23), which promotes left ventricular hypertrophy. Additionally, individuals with ID typically have low circulating levels of vitamin D and an increased body burden of cadmium (Cd). Both factors-high Cd levels and a lack of vitamin D-elevate the risk of various cardiac disorders. Cd is transported in the body via transferrin and as non-transferrin-bound cadmium (NTBCd), with around 50% carried by transferrin. Transferrin-bound Cd is internalized into cells through the transferrin receptor 1 (TfR1), whereas NTBCd uptake occurs via receptors involved in iron transport, such as divalent metal transporter 1 (DMT1), ZIP8, and ZIP14. These receptors, expressed in tissues like the myocardium, contribute to Cd accumulation in the heart. In cases of coronary artery disease, regions of the heart affected by hypoxia, due to reduced blood flow, overexpress TfR1, DMT1, ZIP8, and ZIP14. This increases the uptake of Cd into cardiomyocytes. Cd, once inside the cells, damages mitochondria through oxidative stress, lipid peroxidation, and DNA alterations, leading to cell death. Once destroyed, cardiomyocytes release intracellular potassium which can potentially cause fatal arrhythmia. Cardiac iron bioaccumulation is primarily influenced by two factors: blood iron concentrations and the density of TfR1. Numerous studies have explored the potential benefits of iron supplementation, with varying results. We hypothesize that the extent of beneficial effects from iron supplementation may depend on the presence of specific comorbidities, such as chronic kidney disease or hyperaldosteronism. This hypothesis is based on the observation that certain hormones, including aldosterone and noradrenaline, downregulate the expression of TfR1. Therefore, we propose that co-treatment with iron and aldosterone antagonists could enhance cardiac iron uptake and improve the overall effectiveness of the therapy. Additionally, vitamin D supplementation prior to the onset of disease and chelation therapy after diagnosis could provide some benefits.

Salmonella enterica serovar Typhimurium Effectors spiA and spiC Promote Replication by Modulating Iron Metabolism and Oxidative Stress

Salmonella enterica serovar Typhimurium (S. Typhimurium) poses a major threat to the health and safety of animal-derived foods worldwide. Recently, we have reported that S. Typhimurium uses iron to promote its own proliferation, leading to iron metabolism disorders. However, the mechanism by which S. Typhimurium induces iron metabolism disturbances remains unclear. In this study, we found that the S. Typhimurium effectors spiA and spiC promote the expression of iron regulatory protein 2 (IRP2), transferrin receptor 1 (TfR1) and divalent metal transporter protein 1 (DMT1) and inhibit the expression of ferroportin after transfection with the recombinant plasmids pEGFP-C1-spiA and pEGFP-C1-spiC, which in turn contributes to the accumulation of iron and oxidative stress. Furthermore, we aimed to verify the role of these two effector proteins in S. Typhimurium-induced disorders of iron metabolism. We constructed spiA or spiC mutant strains and their corresponding complementation strains. Our data showed that when spiA or spiC was knocked out, the upregulation of iron metabolism proteins (IRP2, TfR1 and DMT1), the accumulation of iron and oxidative stress caused by the wild-type strain were clearly alleviated in vitro and in vivo, which plays a key role in reducing the intracellular replication of S. Typhimurium and attenuating pathological damage to the liver and ileum of mice. Our findings highlighted that S. Typhimurium induces the disruption of iron metabolism via the virulence factors spiA and spiC, thereby facilitating S. Typhimurium proliferation and causing oxidative damage to the liver and ileum, which provides prospective insights into the search for effective antimicrobial targets for the defense against salmonellosis.

DNMT1-Dependent DNA Methylation of lncRNA FTX Inhibits the Ferroptosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most malignant solid tumors worldwide. Long non-coding RNAs (lncRNAs) are the key factor in the pathogenesis of HCC. This study aimed to investigate the roles of lncRNA FTX transcript, XIST regulator (FTX) in HCC. mRNA levels were detected using RT-qPCR. Protein expression was determined using Western blot. cellular functions were determined using Cell Counting Kit (CCK)-8 and propidium iodide (PI) staining assays. RNA fluorescent in situ hybridization (FISH) assay was conducted to analyze the location of lncRNA FTX and DNMT1. RNA pulldown, RNA immunoprecipitation (RIP), and chromatin-immunoprecipitation (ChIP) assays were used to ascertain the involved mechanisms. We found that FTX was downregulated in HCC patients, which was associated with poor prognosis. Moreover, DNA methyltransferase 1 (DNMT1)-mediated methylation of FTX promoter inhibited its expression. Interestingly, overexpression of FTX promoted the ferroptosis of HCC cells. FTX sponged miR-374b-3p to upregulate transferrin receptor (TFRC) expression. However, downregulation of miR-374b-3p or overexpression of TFRC alleviated the effects of FTX knockdown and promoted the survival of HCC cells. In conclusion, DNMT1-dependent DNA methylation of FTX promotes the development of HCC through regulating miR-374b-3p/TFRC axis. Therefore, DNMT1/FTX/miR-374b-3p/TFRC axis may be a potential target for HCC.