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Xu X, Li Z, Liu H, Huang Z, Xiong T, Tang Y. Gene prediction of the relationship between iron deficiency anemia and immune cells. Hematology 2025; 30:2462857. [PMID: 39957075 DOI: 10.1080/16078454.2025.2462857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/27/2025] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND Observational studies have shown a potential link between immune factors and the risk of iron deficiency anemia (IDA), yet the causal relationship between immune cells and IDA remains enigmatic. Herein, we used Mendelian randomization (MR) to assess whether this association is causal. METHODS We selected IDA genetic variants, including 8376 samples and 9810691 single nucleotide polymorphisms, and immune cells from a large open genome-wide association study (GWAS) for a bidirectional MR study. The primary method was inverse variance weighting (IVW), and auxiliary analyses were MR-Egger, weighted median, simple mode and weighted mode. The reliability of the results was subsequently verified by heterogeneity and sensitivity analysis. RESULTS IVW method showed that 19 types of immune cells may be the risk factors of IDA, whereas 15 types of immune cells are the protective factors of IDA. Reverse MR analysis suggested that immune cells from upstream etiology of IDA are not involved in follow-up immune activities. Next, we selected 731 immune cell types as the results. The research revealed that IDA may result in a rise in 23 kinds of immune cells and a reduction in 12 kinds of immune cells. In addition, sensitivity analysis demonstrated no evidence of heterogeneity or horizontal pleiotropy. CONCLUSIONS From a genetic standpoint, our study suggests that specific immune cells may be involved in the occurrence of IDA. Inversely, IDA may also contribute to immune dysfunction, thus guiding future clinical investigations.
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Affiliation(s)
- Xuanxuan Xu
- Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, People's Republic of China
| | - Zhixia Li
- Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, People's Republic of China
| | - Huimin Liu
- Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, People's Republic of China
| | - Zhiping Huang
- Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, People's Republic of China
| | - Tao Xiong
- Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, People's Republic of China
| | - Yuanyan Tang
- Department of Hematology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, People's Republic of China
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2
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Currie C, Bjerknes C, Nicol M, Kumar S, Framroze B. Assessing the potential for in vivo modulation of FTH1 gene expression with small peptides to restore and enhance androgen receptor pathway inhibition in prostate cancer. Cancer Biol Ther 2025; 26:2503417. [PMID: 40340699 PMCID: PMC12068333 DOI: 10.1080/15384047.2025.2503417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/21/2025] [Accepted: 04/30/2025] [Indexed: 05/10/2025] Open
Abstract
Increased levels of intratumoral free iron drive more aggressive behavior with the development of treatment resistance and spread in a range of cancers including prostate cancer (PCa). This phenotype is associated with an increase in TFRC expression and a decrease in FTH1, a profile supporting increased iron acquisition. In this study we investigated the anti-oncogenic effects of two small peptides (FT-002 and FT-005) that upregulate FTH1 expression and downregulate TFRC expression when combined with standard androgen receptor pathway inhibitors (ARPIs) in xenograft models of PCa in male athymic nude mice. The PC3 cell line was used to establish xenografts representing highly aggressive, androgen-resistant PCa and the LNCaP cell line as a model of androgen-sensitive PCa. Both peptides enhanced the anti-tumor efficacy of ARPI therapy. Efficacy was more marked with the combination of the second-generation APRI enzalutamide than the first-generation agent bicalutamide, a result consistent with known resistance mechanisms to different ARPI therapy. Further, the FT-peptide/enzalutamide combination drove tumor regression whereas enzalutamide monotherapy only slowed growth, even in the hormone-sensitive xenograft. The FT-002a-enzalutamide combination was more effective than FT-005 in reducing tumor mass and volume and modulating FTH1 and TFRC expression. The reversal by the peptides of this oncogenic expression pattern points to a reduction in the tumor free iron via increased iron storage in ferritin and a reduction in iron influx via the transferrin receptor. Peptide-mediated modulation of tumor iron metabolism may therefore offer a novel means to enhance ARPI efficacy and delay resistance in advanced prostate cancer.
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Affiliation(s)
- Crawford Currie
- Research & Development, HBC Immunology Inc, Menlo Park, CA, USA
| | | | - McKayla Nicol
- Research & Development, BioModels LLC, Waltham, MA, USA
| | - Sateesh Kumar
- Research & Development, Adgyl Lifesciences Ltd., Bengaluru, India
| | - Bomi Framroze
- Research & Development, HBC Immunology Inc, Menlo Park, CA, USA
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3
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Gao Q, Zhou Y, Chen Y, Hu W, Jin W, Zhou C, Yuan H, Li J, Lin Z, Lin W. Role of iron in brain development, aging, and neurodegenerative diseases. Ann Med 2025; 57:2472871. [PMID: 40038870 PMCID: PMC11884104 DOI: 10.1080/07853890.2025.2472871] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within the central nervous system, including oxygen transport, energy metabolism, and the synthesis and catabolism of myelin and neurotransmitters. During brain development, iron is distributed throughout the brain, playing a pivotal role in key processes such as neuronal development, myelination, and neurotransmitter synthesis. In physiological aging, iron can selectively accumulate in specific brain regions, impacting cognitive function and leading to intracellular redox imbalance, mitochondrial dysfunction, and lipid peroxidation, thereby accelerating aging and associated pathologies. Furthermore, brain iron accumulation may be a primary contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Comprehending the role of iron in brain development, aging, and neurodegenerative diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction of abnormal neurological states, and implementing appropriate interventions may be instrumental in preserving normal central nervous system function.
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Affiliation(s)
- Qiqi Gao
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yiyang Zhou
- Department of Urology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Yu Chen
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Hu
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenwen Jin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Chunting Zhou
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hao Yuan
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianshun Li
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhenlang Lin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Lin
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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4
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Bhatnagar K, Raju S, Patki N, Motiani RK, Chaudhary S. Targeting mineral metabolism in cancer: Insights into signaling pathways and therapeutic strategies. Semin Cancer Biol 2025; 112:1-19. [PMID: 40024314 DOI: 10.1016/j.semcancer.2025.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/29/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025]
Abstract
Cancer remains the second leading cause of death worldwide, emphasizing the critical need for effective treatment and control strategies. Essential minerals such as copper, iron, zinc, selenium, phosphorous, calcium, and magnesium are integral to various biological processes and significantly influence cancer progression through altered metabolic pathways. For example, dysregulated copper levels promote tumor growth, while cancer cells exhibit an increased dependency on iron for signaling and redox reactions. Zinc influences tumor development through pathways such as Akt-p21. Selenium, primarily through its role in selenoproteins, exhibits anticancer potential but may also contribute to tumor progression. Similarly, dietary phosphate exacerbates tumorigenesis, metastasis, and angiogenesis through signaling pathway activation. Calcium, the most abundant mineral in the body, is tightly regulated within cells, and its dysregulation is a hallmark of various cancers. Magnesium deficiency, on the other hand, promotes cancer progression by fostering inflammation and free radical-induced DNA mutations. Interestingly, magnesium also plays a dual role, with low levels enhancing epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis. This complex interplay of essential minerals underscores their potential as therapeutic targets. Dysregulation of these minerals and their pathways could be exploited to selectively target cancer cells, offering novel therapeutic strategies. This review summarizes current research on the abnormal accumulation or depletion of these microelements in tumor biology, drawing evidence from animal models, cell lines, and clinical samples. We also highlight the potential of these minerals as biomarkers for cancer diagnosis and prognosis, as well as therapeutic approaches involving metal chelators, pharmacological agents, and nanotechnology. By highlighting the intricate roles of these minerals in cancer biology, we aim to inspire further research in this critical yet underexplored area of oncology.
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Affiliation(s)
- Kartik Bhatnagar
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
| | - Sharon Raju
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-Gurugram Expressway, Faridabad, Haryana 121001, India.
| | - Ninad Patki
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
| | - Rajender K Motiani
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-Gurugram Expressway, Faridabad, Haryana 121001, India.
| | - Sarika Chaudhary
- Department of Biotechnology, School of Engineering and Applied Sciences, Bennett University, Plot Nos. 8-11, Tech Zone 2, Greater Noida, Uttar Pradesh 201310, India.
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Cozzi A, Santambrogio P, Moro AS, Pelagatti A, Rubio A, Balestrucci C, Di Meo I, Tiranti V, Levi S. Fibroblasts and hiPS-Derived Astrocytes From CoPAN Patients Showed Different Levels of Iron Overload Correlated With Senescent Phenotype. Glia 2025; 73:1467-1482. [PMID: 40105046 PMCID: PMC12121470 DOI: 10.1002/glia.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/05/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025]
Abstract
COASY protein-associated neurodegeneration (CoPAN) is a rare autosomal recessive disorder within the Neurodegeneration with Brain Iron Accumulation spectrum, resulting from mutations in COASY. This gene encodes the bifunctional enzyme essential for the final steps of coenzyme A biosynthesis. To elucidate the pathophysiology and iron dyshomeostasis underlying CoPAN, we analyzed fibroblasts and human induced pluripotent stem (hiPS)-derived astrocytes from two patients carrying distinct COASY mutations. Our findings reveal that CoPAN fibroblasts display altered iron homeostasis, characterized by iron aggregates, elevated cytosolic labile iron pool, and impaired tubulin acetylation. Patients hiPS-derived astrocytes showed mitochondrial morphological abnormalities and compromised vesicular trafficking. Notably, both cell types demonstrated evidence of ferroptosis, but the astrocytes exhibited more pronounced iron accumulation and lipid peroxidation. These results demonstrate that astrocytes may more accurately recapitulate the pathological phenotype of CoPAN compared to fibroblasts. Interestingly, astrocytes exhibited different levels of iron accumulation concomitant with cellular senescence, indicating a possible role of iron-induced cellular senescence. This finding suggests that the accumulation of cytosolic iron, possibly caused by mitochondrial dysfunction, actively promotes senescence. Our data emphasize the potential therapeutic efficacy of drugs that enhance mitochondrial functionality to attenuate the effects of CoPAN.
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Affiliation(s)
- Anna Cozzi
- Division of NeuroscienceIRCCS San Raffaele Scientific InstituteMilanItaly
| | - Paolo Santambrogio
- Division of NeuroscienceIRCCS San Raffaele Scientific InstituteMilanItaly
| | | | - Alessio Pelagatti
- Division of NeuroscienceIRCCS San Raffaele Scientific InstituteMilanItaly
| | - Alicia Rubio
- Institute of Neuroscience, National Research CouncilMilanItaly
- IFOMMilanItaly
| | | | - Ivano Di Meo
- Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
| | - Valeria Tiranti
- Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
| | - Sonia Levi
- Division of NeuroscienceIRCCS San Raffaele Scientific InstituteMilanItaly
- Vita‐Salute San Raffaele UniversityMilanItaly
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Nolte S, Malhan D, Klemmer A, Kastner T, Walter N, Fleckenstein D, Keck J, Klügel S, Maier C, Gebhardt K, Stauber T, Relógio A, Krüger K, Hollander K. Training in normobaric hypoxia induces hematological changes that affect iron metabolism and immunity. Sci Rep 2025; 15:17757. [PMID: 40404671 PMCID: PMC12098981 DOI: 10.1038/s41598-025-01542-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 05/06/2025] [Indexed: 05/24/2025] Open
Abstract
Altitude training is a method among endurance athletes to enhance performance via hypoxia-induced adaptations. However, individual responses vary significantly, with some athletes even showing performance decrements. Iron metabolism and immune function may influence these adaptations, as hypoxia-induced erythropoiesis increases systemic iron demand, potentially affecting immune cells reliant on iron. This study investigated the interplay between hematological, iron, and immunological variables under controlled normobaric hypoxia. 15 highly trained athletes participated in a 21-day live-high-train-low training camp in a normobaric altitude house. Blood samples were collected pre- and post-camp and at four intermediate time points to measure hematological variables, iron metabolism variables, and immunological variables. Pre- and post-performance was assessed via VO2max tests. Statistical analyses included paired t-tests, Wilcoxon rank-sum test, Spearman correlations, and Granger causality analysis to explore systemic temporal interactions. VO2max increased significantly (p < 0.05) with large interindividual variability (2.4 ± 3.5 ml/min/kg). Hemoglobin concentration, erythrocytes, and the soluble transferrin receptor (sTfR) showed significant increases over time (p < 0.05), while ferritin peaked early and declined post-camp. Myeloperoxidase and lactoferrin exhibited dynamic correlations with iron variables (p < 0.05), reflecting competition between erythropoiesis and immune function for iron. The structure of the Granger causality network places transferrin in a central role, highlighting iron metabolism as one key regulator of these adaptations. Normobaric hypoxia training induces systemic physiological changes involving hematological, iron, and immune systems. Controlled hypoxic conditions enable detailed exploration of these interactions, providing insights into optimizing altitude training strategies for endurance performance enhancement.
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Affiliation(s)
- Svenja Nolte
- Department of Exercise Physiology and Sports Therapy, Institute of Sport Science, Justus-Liebig-University Giessen, Giessen, Germany
- Institute of Interdisciplinary Exercise Science and Sports Medicine, Medical School Hamburg, Hamburg, Germany
| | - Deeksha Malhan
- Institute for Systems Medicine, Medical School Hamburg, Hamburg, Germany
| | - Anna Klemmer
- Institute for Molecular Medicine, Medical School Hamburg, Hamburg, Germany
| | - Tom Kastner
- Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Sports Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Institute for Applied Training Science, Leipzig, Germany
| | - Nico Walter
- Institute for Applied Training Science, Leipzig, Germany
| | | | - Johannes Keck
- Department of Exercise Physiology and Sports Therapy, Institute of Sport Science, Justus-Liebig-University Giessen, Giessen, Germany
| | - Simon Klügel
- Department of Exercise Physiology and Sports Therapy, Institute of Sport Science, Justus-Liebig-University Giessen, Giessen, Germany
| | - Celina Maier
- Department of Exercise Physiology and Sports Therapy, Institute of Sport Science, Justus-Liebig-University Giessen, Giessen, Germany
| | - Kristina Gebhardt
- Department of Exercise Physiology and Sports Therapy, Institute of Sport Science, Justus-Liebig-University Giessen, Giessen, Germany
| | - Tobias Stauber
- Institute for Molecular Medicine, Medical School Hamburg, Hamburg, Germany
| | - Angela Relógio
- Institute for Systems Medicine, Medical School Hamburg, Hamburg, Germany
| | - Karsten Krüger
- Department of Exercise Physiology and Sports Therapy, Institute of Sport Science, Justus-Liebig-University Giessen, Giessen, Germany.
| | - Karsten Hollander
- Institute of Interdisciplinary Exercise Science and Sports Medicine, Medical School Hamburg, Hamburg, Germany
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7
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Jiang X, Ren Y, Huang C, Hu S, Gao Z, Gao J, Ma D, Liu G. ZnO Nanoparticle Exposure Disrupted Iron-Sulfur Protein Functions to Increase Macrophage Erythrophagocytosis and Disturb Systemic Iron Recycling. ACS NANO 2025; 19:18450-18465. [PMID: 40333237 DOI: 10.1021/acsnano.5c01592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Although anemia is a common systemic toxicological manifestation of zinc product overload, the underlying mechanisms remain elusive. Therefore, we explored the mechanisms underlying the anemia caused by exposure to zinc oxide nanoparticles (ZnO NPs), which are a widely utilized Zn product. We observed that ZnO NP-exposed mice developed evident anemia due to disrupted spleen iron metabolism. Since spleen iron metabolism relies on macrophages, we further investigated how ZnO NP exposure affected macrophage function. Results indicated that ZnO NP exposure triggered macrophage metabolic reprogramming to facilitate erythrophagocytosis and blunted the response of iron exporter ferroportin to enhanced erythrophagocytosis, thereby causing iron retention and ultimately impeding macrophage iron recycling. Mechanistically, Zn2+ released from ZnO NPs occupied the cluster-binding cysteines of iron-sulfur proteins, regulating glucose metabolism and ferroportin expression to suppress their activity, thereby inducing metabolic reprogramming and suppressing iron export. Our research unveils a category of nanobio interactions underlying ZnO NPs biotoxicity.
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Affiliation(s)
- Xiumei Jiang
- School of Chemistry, Northeast Normal University, Changchun 130024, China
| | - Yujie Ren
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China
| | - Chengquan Huang
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China
| | - Shunchang Hu
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China
| | - Zitong Gao
- School of Chemistry, Northeast Normal University, Changchun 130024, China
| | - Jianmin Gao
- School of Chemistry, Northeast Normal University, Changchun 130024, China
| | - Dongxiao Ma
- Department of Clinical Laboratory, the First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Gang Liu
- Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China
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8
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Khan MA. Iron responsive elements mRNA regulate Alzheimer's amyloid precursor protein translation through iron sensing. Front Aging Neurosci 2025; 17:1483913. [PMID: 40438504 PMCID: PMC12116395 DOI: 10.3389/fnagi.2025.1483913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 04/23/2025] [Indexed: 06/01/2025] Open
Abstract
Iron responsive element (IREs) mRNA and iron regulatory proteins (IRPs) regulate iron homeostasis. 5'-untranslated region motifs of APP IREs fold into RNA stem loops bind to IRP to control translation. Through the 5'-UTR APP IREs, iron overload accelerated the translation of the Alzheimer's amyloid precursor protein (APP). The protein synthesis activator eIF4F and the protein synthesis repressor IRP1 are the two types of proteins that IREs bind. Iron regulates the competitive binding of eIF4F and IRP1 to IRE. Iron causes the IRE and eIF4F to associate with one other, causing the dissociation of IRPs and altered translation. In order to control IRE-modulated expression of APP, messenger RNAs are becoming attractive targets for the development of small molecule therapeutics. Many mRNA interference strategies target the 2-D RNA structure, but messenger RNAs like rRNAs and tRNAs can fold into complicated, three-dimensional structures that add another level of complexity. IREs family is one of the few known 3-D mRNA regulatory elements. In this review, I present IREs structural and functional characteristics. For iron metabolism, the mRNAs encoding the proteins are controlled by this family of similar base sequences. Iron has a similar way of controlling the expression of Alzheimer's APP as ferritin IRE RNA in their 5ÚTR. Further, iron mis regulation by IRPs can be investigated and contrasted using measurements of expression levels of APP, amyloid-β and tau formation. Accordingly, IRE-modulated APP expression in Alzheimer's disease has great therapeutic potential through targeting mRNA structures.
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Affiliation(s)
- Mateen A. Khan
- Department of Life Science, College of Science and General Studies, Alfaisal University, Riyadh, Saudi Arabia
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Cuisiniere T, Hajjar R, Oliero M, Calvé A, Fragoso G, Rendos HV, Gerkins C, Taleb N, Gagnon-Konamna M, Dagbert F, Loungnarath R, Sebajang H, Schwenter F, Wassef R, Ratelle R, De Broux É, Richard C, Santos MM. Initial gut microbiota composition is a determining factor in the promotion of colorectal cancer by oral iron supplementation: evidence from a murine model. MICROBIOME 2025; 13:100. [PMID: 40259408 PMCID: PMC12013013 DOI: 10.1186/s40168-025-02101-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/26/2025] [Indexed: 04/23/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) development is influenced by both iron and gut microbiota composition. While iron supplementation is routinely used to manage anemia in CRC patients, it may also impact gut microbiota and promote tumorigenesis. In this study, we investigated the impact of initial gut microbiota composition on iron-promoted tumorigenesis. We performed fecal microbiota transplantation (FMT) in ApcMin/+ mice using samples from healthy controls, CRC patients, and mice, followed by exposure to iron sufficient or iron excess diets. RESULTS We found that iron supplementation promoted CRC and resulted in distinct gut microbiota changes in ApcMin/+ mice receiving FMT from CRC patients (FMT-CRC), but not from healthy controls or mice. Oral treatment with identified bacterial strains, namely Faecalibaculum rodentium, Holdemanella biformis, Bifidobacterium pseudolongum, and Alistipes inops, protected FMT-CRC mice against iron-promoted tumorigenesis. CONCLUSIONS Our findings suggest that microbiota-targeted interventions may mitigate tumorigenic effects of iron supplementation in anemic patients with CRC.
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Affiliation(s)
- Thibault Cuisiniere
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Roy Hajjar
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Department of Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Manon Oliero
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Annie Calvé
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Gabriela Fragoso
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Hervé Vennin Rendos
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Claire Gerkins
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Nassima Taleb
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Marianne Gagnon-Konamna
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - François Dagbert
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Rasmy Loungnarath
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Herawaty Sebajang
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Frank Schwenter
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Ramses Wassef
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Richard Ratelle
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Éric De Broux
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Carole Richard
- Digestive Surgery Service, Centre Hospitalier de L'Université de Montréal (CHUM), Montréal, Québec, Canada
- Division of General Surgery, Université de Montréal, Montréal, Québec, Canada
| | - Manuela M Santos
- Nutrition and Microbiome Laboratory, Centre de Recherche du Centre hospitalier de l', Université de Montréal (CRCHUM), Montréal, Québec, Canada.
- Institut du Cancer de Montréal, Montréal, Québec, Canada.
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.
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Zhao N, Li S, Wu H, Wei D, Pu N, Wang K, Liu Y, Tao Y, Song Z. Ferroptosis: An Energetic Villain of Age-Related Macular Degeneration. Biomedicines 2025; 13:986. [PMID: 40299661 PMCID: PMC12024642 DOI: 10.3390/biomedicines13040986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 04/01/2025] [Accepted: 04/14/2025] [Indexed: 05/01/2025] Open
Abstract
Iron homeostasis plays an important role in maintaining cellular homeostasis; however, excessive iron can promote the production of reactive oxygen species (ROS). Ferroptosis is iron-dependent programmed cell death that is characterized by excessive iron accumulation, elevated lipid peroxides, and the overproduction of ROS. The maintenance of iron homeostasis is contingent upon the activity of the transferrin receptor (TfR), ferritin (Ft), and ferroportin (FPn). In the retina, iron accumulation and lipid peroxidation can contribute to the development of age-related macular degeneration (AMD). This phenomenon can be explained by the occurrence of the Fenton reaction, in which the interaction between divalent iron and hydrogen peroxide leads to the generation of highly reactive hydroxyl radicals. The hydroxyl radicals exhibit a propensity to attack proteins, lipids, nucleic acids, and carbohydrates, thereby instigating oxidative damage and promoting lipid peroxidation. Ultimately, these processes culminate in cell death and retinal degeneration. In this context, a comprehensive understanding of the exact mechanisms underlying ferroptosis may hold significant importance for developing therapeutic interventions. This review summarizes recent findings on iron metabolism, cellular ferroptosis, and lipid metabolism in the aging retina. We also introduce developments in the therapeutic strategies using iron chelating agents. Further refinements of these knowledges would deepen our comprehension of the pathophysiology of AMD and advance the clinical management of degenerative retinopathy. A comprehensive search strategy was employed to identify relevant studies on the role of ferroptosis in AMD. We performed systematic searches of the PubMed and Web of Science electronic databases from inception to the current date. The keywords used in the search included "ferroptosis", "AMD", "age-related macular degeneration", "iron metabolism", "oxidative stress", and "ferroptosis pathways". Peer-reviewed articles, including original research, reviews, meta-analyses, and clinical studies, were included in this paper, with a focus on the molecular mechanisms of ferroptosis in AMDs. Studies not directly related to ferroptosis, iron metabolism, or oxidative stress in the context of AMD were excluded. Furthermore, articles that lacked sufficient data or were not peer-reviewed (e.g., conference abstracts, editorials, or opinion pieces) were not considered.
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Affiliation(s)
- Na Zhao
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan University School of Medicine, Henan Provincial People’s Hospital, Zhengzhou 450003, China; (N.Z.); (K.W.); (Y.L.)
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China; (S.L.); (H.W.); (D.W.); (N.P.)
| | - Siyu Li
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China; (S.L.); (H.W.); (D.W.); (N.P.)
| | - Hao Wu
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China; (S.L.); (H.W.); (D.W.); (N.P.)
| | - Dong Wei
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China; (S.L.); (H.W.); (D.W.); (N.P.)
| | - Ning Pu
- College of Medicine, Zhengzhou University, Zhengzhou 450001, China; (S.L.); (H.W.); (D.W.); (N.P.)
| | - Kexin Wang
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan University School of Medicine, Henan Provincial People’s Hospital, Zhengzhou 450003, China; (N.Z.); (K.W.); (Y.L.)
| | - Yashuang Liu
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan University School of Medicine, Henan Provincial People’s Hospital, Zhengzhou 450003, China; (N.Z.); (K.W.); (Y.L.)
| | - Ye Tao
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan University School of Medicine, Henan Provincial People’s Hospital, Zhengzhou 450003, China; (N.Z.); (K.W.); (Y.L.)
| | - Zongming Song
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan University School of Medicine, Henan Provincial People’s Hospital, Zhengzhou 450003, China; (N.Z.); (K.W.); (Y.L.)
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11
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De T, Coin L, Herberg J, Johnson MR, Järvelin MR. Plasma metabolomic signatures for copy number variants and COVID-19 risk loci in Northern Finland populations. Sci Rep 2025; 15:13172. [PMID: 40240424 PMCID: PMC12003712 DOI: 10.1038/s41598-025-94839-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
Copy number variants (CNVs) are an important class of genomic variation known to be important for human physiology and diseases. Here we present genome-wide metabolomic signatures for CNVs in two Finnish cohorts-The Northern Finland Birth Cohort 1966 (NFBC 1966) and NFBC 1986. We have analysed and reported CNVs in over 9,300 individuals and characterised their dosage effect (CNV-metabolomic QTL) on 228 plasma lipoproteins and metabolites. We have reported reference (normal physiology) metabolomic signatures for up to ~ 2.6 million COVID-19 GWAS results from the National Institutes of Health (NIH) GRASP database, including for outcomes related to COVID-19 death, severity, and hospitalisation. Furthermore, by analysing two exemplar genes for COVID-19 severity namely LZTFL1 and OAS1, we have reported here two additional candidate genes for COVID-19 severity biology, (1) NFIX, a gene related to viral (adenovirus) replication and hematopoietic stem cells and (2) ACSL1, a known candidate gene for sepsis and bacterial inflammation. Based on our results and current literature we hypothesise that (1) charge imbalance across the cellular membrane between cations (Fe2+, Mg2+ etc.) and anions (e.g. ROS, hydroxide ion from cellular Fenton reactions, superoxide etc.), (2) iron trafficking within and between different cell types e.g., macrophages and (3) systemic oxidative stress response (e.g. lipid peroxidation mediated inflammation), together could be of relevance in severe COVID-19 cases. To conclude, our unique atlas of univariate and multivariate metabolomic signatures for CNVs (~ 7.2 million signatures) with deep annotations of various multi-omics data sets provide an important reference knowledge base for human metabolism and diseases.
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Affiliation(s)
- Tisham De
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
- Department of Genomics of Common Diseases, Imperial College London, London, UK.
- Department of Infectious Disease, Imperial College London, London, UK.
| | - Lachlan Coin
- Department of Infectious Disease, Imperial College London, London, UK
- Department of Microbiology and Immunology, Institute for Infection and Immunity, University of Melbourne at The Peter Doherty, Melbourne, Australia
| | - Jethro Herberg
- Department of Infectious Disease, Imperial College London, London, UK
| | | | - Marjo-Riitta Järvelin
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Centre for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Unit of Primary Health Care and Medical Research Center, Oulu University Hospital, Oulu, Finland
- Centre for Environment and Health, Imperial College London, London, UK
- Biocenter Oulu, University of Oulu, Oulu, Finland
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12
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Pei Y, Yin Z, Xu T, Dou D. Relay model: bridging ligands and receptors in networks. TRENDS IN PLANT SCIENCE 2025:S1360-1385(25)00095-0. [PMID: 40240258 DOI: 10.1016/j.tplants.2025.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025]
Abstract
Transmembrane-receptor-mediated recognition is fundamental to signaling and nutrient transport in diverse biological systems. While traditional models involve direct ligand-receptor binding, emerging evidence supports a relay model, in which substrate-binding proteins transfer ligands to receptors or form cooperative receptor complexes. This mechanism enhances the specificity and versatility of the ligand-receptor network.
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Affiliation(s)
- Yong Pei
- State Key Laboratory of Agricultural and Forestry Biosecurity, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhiyuan Yin
- State Key Laboratory of Agricultural and Forestry Biosecurity, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China.
| | - Tongda Xu
- State Key Laboratory of Agricultural and Forestry Biosecurity, College of Horticulture, School of Future Technology, and Haixia Institute of Science and Technology, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Daolong Dou
- State Key Laboratory of Agricultural and Forestry Biosecurity, College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China; Academy for Advanced Interdisciplinary Studies, Nanjing Agricultural University, Nanjing 210095, China
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13
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Mao N, Zhang M, Shen M, Yuan J, Lin Z. Research progress on ferroptosis in cerebral hemorrhage. Biomed Pharmacother 2025; 185:117932. [PMID: 40015051 DOI: 10.1016/j.biopha.2025.117932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 02/06/2025] [Accepted: 02/15/2025] [Indexed: 03/01/2025] Open
Abstract
The pathophysiology of intracerebral hemorrhage (ICH) is complex and can cause variable degrees of cell death. Recently, ferroptosis, an emerging cell death mechanism, has garnered significant attention in cerebral hemorrhage disorder. This study aimed to examine iron mortality after cerebral hemorrhage and current targets for potential therapeutic interventions. We specifically focused on iron metabolism abnormalities, lipid peroxidation, and related neuroinflammation and introduced molecular mechanisms, including transcription factors, to gain a better understanding of the underlying mechanisms of ferroptosis and investigate possible therapeutic options for ICH.
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Affiliation(s)
- Niping Mao
- Department of Neonatology, the Second School of Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Perinatal Medicine of Wenzhou, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Min Zhang
- Department of Neonatology, the Second School of Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Perinatal Medicine of Wenzhou, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming Shen
- Department of Neonatology, the Second School of Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Perinatal Medicine of Wenzhou, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Junhui Yuan
- Department of Neonatology, Wenling maternal and child health care hospital, Wenling, Zhejiang, China.
| | - Zhenlang Lin
- Department of Neonatology, the Second School of Medicine, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Perinatal Medicine of Wenzhou, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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14
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Bolesławska I, Bolesławska-Król N, Jakubowski K, Przysławski J, Drzymała-Czyż S. Lactoferrin-A Regulator of Iron Homeostasis and Its Implications in Cancer. Molecules 2025; 30:1507. [PMID: 40286136 PMCID: PMC11990823 DOI: 10.3390/molecules30071507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
Cancer is a global health challenge, and its development is closely linked to iron metabolism. Cancer cells have an increased demand for this element, which promotes their proliferation, invasion, and metastasis. Excess iron catalyzes the formation of reactive oxygen species (ROS), which can both induce ferroptosis and initiate oncogenic signaling pathways. The deregulation of iron metabolism in cancer patients leads to anemia or toxic iron overload and also affects the gut microbiota. Lactoferrin (LF), a glycoprotein with strong iron chelating properties, can regulate its availability to cancer cells, thereby limiting their growth and progression. By chelating free Fe ions, LF reduces oxidative stress and inhibits the mechanisms that promote carcinogenesis. Additionally, it exhibits immunomodulatory and anti-inflammatory effects and may enhance the body's anti-tumor response. This review analyses the mechanisms of action of lactoferrin in the context of cancer, with a particular focus on its chelating, antioxidant, and immunomodulatory properties. The multidirectional effects of LF make it a promising component of preventive and therapeutic strategies, requiring further clinical studies.
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Affiliation(s)
- Izabela Bolesławska
- Department of Bromatology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.J.); (J.P.); (S.D.-C.)
| | - Natasza Bolesławska-Król
- Student Society of Radiotherapy, Collegium Medicum, University of Zielona Góra, Zyta 28, 65-046 Zielona Góra, Poland;
| | - Karol Jakubowski
- Department of Bromatology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.J.); (J.P.); (S.D.-C.)
| | - Juliusz Przysławski
- Department of Bromatology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.J.); (J.P.); (S.D.-C.)
| | - Sławomira Drzymała-Czyż
- Department of Bromatology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; (K.J.); (J.P.); (S.D.-C.)
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15
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Zhou X, Tian L, Xiong W, Li Y, Liu Q. Ferroptosis and hyperoxic lung injury: insights into pathophysiology and treatment approaches. Front Pharmacol 2025; 16:1568246. [PMID: 40170719 PMCID: PMC11958998 DOI: 10.3389/fphar.2025.1568246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/04/2025] [Indexed: 04/03/2025] Open
Abstract
Hyperoxia therapy is a critical clinical intervention for both acute and chronic illnesses. However, prolonged exposure to high-concentration oxygen can cause lung injury. The mechanisms of hyperoxic lung injury (HLI) remain incompletely understood, and current treatment options are limited. Improving the safety of hyperoxia therapy has thus become an urgent priority. Ferroptosis, a novel form of regulated cell death characterized by iron accumulation and excessive lipid peroxidation, has been implicated in the pathogenesis of HLI, including diffuse alveolar damage, vascular endothelial injury, and bronchopulmonary dysplasia. In this review, we analyze the latest findings on ferroptosis and therapeutic strategies for HLI. Our aim is to provide new insights for the treatment of HLI and to facilitate the translation of these findings from bench to bedside.
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Affiliation(s)
- Xiaoqiong Zhou
- Department of Anesthesiology, Zigong First People’s Hospital, Zigong Academy of Medical Sciences, Zigong, China
| | - Lei Tian
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Wenyan Xiong
- Department of Anesthesiology, Yibin Maternity and Children Hospital, Yibin, China
| | - Yulan Li
- Department of Anesthesiology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Qian Liu
- Department of Anesthesiology, Zigong First People’s Hospital, Zigong Academy of Medical Sciences, Zigong, China
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16
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Chu MQ, Zhang TJ, Liu ZQ, Yang Q, Du TT, Zhang MJ, Jin Y, Cao YJ, Wen XM, Xu ZJ, Zhao YJ, Lin J, Qian J, Zhou JD. MiR-218 Exhibits Anti-Leukemia Effects by Targeting CTNND2 in Primary Acute Erythroid Leukemia HEL Cells. Cell Biochem Biophys 2025:10.1007/s12013-025-01722-5. [PMID: 40100342 DOI: 10.1007/s12013-025-01722-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2025] [Indexed: 03/20/2025]
Abstract
Acute erythroid leukemia (AEL) is a rare acute myeloid leukemia (AML) subtype that is highly aggressive and is associated with a poor prognosis. Notably, the blockage of erythroid differentiation represents a significant factor in the pathogenesis of erythroleukemia. Prior studies indicated that miR-218 inhibited the erythroid differentiation in a chronic myeloid leukemia (CML)-derived erythroleukemia cell line K562. However, functions of miR-218 in primary AEL remains to be elucidated. To address this gap, functions of miR-218 in HEL cells were evaluated through cell differentiation, cell proliferation, colony formation, cell cycle and cell apoptosis experiments. Subsequently, the targeted downstream genes of miR-218 were identified by the transcriptome sequencing and bioinformatic research, of which demonstrated by the dual-luciferase reporter experiment. Finally, the underlying mechanism of miR-218 in leukemogenesis was identified by enrichment analysis and was validated by western blot (WB) assays. Intriguingly, enhanced miR-218 showed no effect on the erythroid differentiation in HEL cells by determination of the expression of erythroid markers including GATA1, KLF1, TFRC and GYPA. However, miR-218 overexpression in HEL cells presented a markedly anti-proliferative and pro-apoptotic effects, inhibited colony formation and G0/G1 arrest. Transcriptome sequencing and bioinformatics analysis revealed that CTNND2 as the candidate gene of miR-218 within its 3'-untranslated region (3'-UTR) could be bonded by it. Reduced expression level of CTNND2 was further demonstrated by quantitative-PCR and WB after miR-218 overexpression in HEL cells. Furthermore, the luciferase report assay revealed that the CTNND2 production was reduced with its 3'-UTR region was bonded by miR-218. In addition, MAPK signaling pathway was identified and validated as the potential functional pathway involved in leukemogenesis caused by miR-218 overexpression in HEL cells. In summary, miR-218 exhibits anti-proliferative and pro-apoptotic functions by targeting CTNND2 and modulating MAPK signaling in HEL cells, yet it has no impact on the erythroid differentiation process.
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Affiliation(s)
- Ming-Qiang Chu
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Ting-Juan Zhang
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Department of Oncology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Zi-Qi Liu
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Department of Nephrology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Qian Yang
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Ting-Ting Du
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Min-Jie Zhang
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Ye Jin
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Yong-Jie Cao
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Xiang-Mei Wen
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Zi-Jun Xu
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Yang-Jing Zhao
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Jiang Lin
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
- Laboratory Center, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Jun Qian
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China
| | - Jing-Dong Zhou
- Department of Hematology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
- Institute of Hematology, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China.
- Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China.
- The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China.
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17
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Ben Zichri- David S, Shkuri L, Ast T. Pulling back the mitochondria's iron curtain. NPJ METABOLIC HEALTH AND DISEASE 2025; 3:6. [PMID: 40052109 PMCID: PMC11879881 DOI: 10.1038/s44324-024-00045-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 12/09/2024] [Indexed: 03/09/2025]
Abstract
Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.
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Affiliation(s)
| | - Liraz Shkuri
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001 Israel
| | - Tslil Ast
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 7610001 Israel
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18
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Kotak K, Aggarwal K, Garg S, Gupta V, Anamika F, Jain R. Understanding the Interplay between Iron Deficiency and Congestive Heart Failure: A comprehensive review. Cardiol Rev 2025; 33:171-177. [PMID: 37643208 DOI: 10.1097/crd.0000000000000603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Iron is an essential micronutrient for abounding physiological processes in the body, and its deficiency can be caused by various factors, such as low iron intake due to economic difficulties or loss of appetite, decreased iron absorption due to gastrointestinal issues, or increased iron loss due to hemorrhages or proteinuria. Iron deficiency is a prevalent issue among heart failure (HF) patients and is a significant contributor to anemia, affecting 30-50% of patients regardless of their gender, ethnicity, or left ventricular ejection fraction. Individuals with HF have high levels of pro-inflammatory cytokines, which can inhibit erythropoiesis by degrading the membrane iron exporter ferroportin, mediated by an increased release of hepcidin. In addition, elevated sympathetic and renin-angiotensin-aldosterone system activity retains salt and water, resulting in high cardiac output HF in people with normal left ventricular function. This review provides an overview of iron deficiency and HF.
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Affiliation(s)
- Kopal Kotak
- From the Department of Internal Medicine, Pandit Dindayal Upadhyay Medical College, Gujarat, India
| | - Kanishk Aggarwal
- Department of Internal Medicine, Dayanand Medical College and Hospital, Punjab, India
| | - Shreya Garg
- Department of Internal Medicine, Dayanand Medical College and Hospital, Punjab, India
| | - Vasu Gupta
- Department of Internal Medicine, Dayanand Medical College and Hospital, Punjab, India
| | - Fnu Anamika
- Department of Internal Medicine, University College of Medical Sciences, New Delhi, India
| | - Rohit Jain
- Department of Internal Medicine, Penn State Milton S. Hershey Medical Center, PA
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19
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Zhu F, Ren L, Cheng W, Zhou H, Li Y, Liu N, Rong G, Liu Y, Yu P, Lv J, Cheng Y, Chen C. A Dynamic Deferoxamine Polymer with Exceptional Performance in Mitochondrial Iron Depletion and Cytosolic Protein Delivery. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2412093. [PMID: 39945100 DOI: 10.1002/smll.202412093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/02/2025] [Indexed: 03/20/2025]
Abstract
Deferoxamine (DFO) is an FDA-approved naturally occurring iron chelator commonly used to treat transfusion-induced iron overload. The abundant and flexible hydroxamic acid groups in DFO enable exceptional iron binding capacity and high protein binding via hydrogen bonding interactions. However, the applications of DFO to sequester intracellular iron and to deliver proteins inside cells are limited due to poor membrane-permeability. Herein, the fabrication of a dynamic DFO polymer is proposed to achieve robust intracellular protein delivery and efficient mitochondrial iron depletion. Specifically, DFO is grafted onto a polycatechol scaffold via dynamic catechol-boronate chemistry. The obtained DFO polymer shows robust protein binding capacity, and the formed protein complexes show high resistance toward serum proteins. It effectively delivers various cargo proteins into cytosol of treated cells with maintained bioactivity. In addition, the polymer delivers DFO inside cells, and the released DFO efficiently depletes mitochondrial iron, which significantly inhibits mitochondrial oxidative phosphorylation and glycolysis. Remarkable synergistic cytotoxic effects are achieved when the DFO polymer is loaded with toxic proteins. This study provides a general strategy for facile preparation of bioactive polymer toward robust protein delivery, and the designed polymer can be a promising carrier for the delivery of protein therapeutics to treat cancer.
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Affiliation(s)
- Fang Zhu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Lanfang Ren
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Wenhua Cheng
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Haohan Zhou
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
- Department of Orthopedic Oncology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China
| | - Yuhan Li
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Nan Liu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
- Department of Ophthalmology and Vision Science, Shanghai Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, 200030, China
| | - Guangyu Rong
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
- Department of Ophthalmology and Vision Science, Shanghai Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, 200030, China
| | - Yunfeng Liu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Panting Yu
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Jia Lv
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yiyun Cheng
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Chao Chen
- Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China
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20
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Dev S, Asthana S, Singh P, Seth P, Banerjee C, Mukhopadhyay CK. Dopamine degrades ferritin by chaperone-mediated autophagy to elevate mitochondrial iron level in astroglial cells. Free Radic Biol Med 2025; 229:39-57. [PMID: 39818240 DOI: 10.1016/j.freeradbiomed.2025.01.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/05/2025] [Accepted: 01/13/2025] [Indexed: 01/18/2025]
Abstract
Iron accumulation and mitochondrial dysfunction in astroglia are reported in Parkinson's disease (PD). Astroglia control iron availability in neurons in which dopamine (DA) synthesis is affected in PD. Despite their intimate relationship the role of DA in astroglial iron homeostasis is limited. Here we show that DA degrades iron storage protein ferritin in astroglial cells involving lysosomal proteolysis. Lysosomal ferritinophagy is mainly associated with macroautophagy; however, we revealed the involvement of chaperone-mediated autophagy (CMA) in DA-induced ferritin degradation. In CMA, cytosolic proteins containing a specific pentapeptide motif bind with HSC70 to be transported to lysosome mediated by LAMP2A. We identified the conserved pentapeptide motif in ferritin-H (Ft-H), mutations of which resulted loss of its interaction with HSC70. Pharmacological inhibitors of HSC70 or LAMP2/2A knockdown blocks DA-induced Ft-H degradation. DA also induces cytosolic cargo NCOA4 for ferritinophagy. We further reveal that DA promotes cathepsin B to lysis ferritin within the lysosome. Inhibitor of cathepsin B, knocking down of LAMP2, or HSC70 inhibitor attenuate DA-induced elevated mitochondrial iron level. Our results establish a direct role of DA on astroglial iron homeostasis and novel involvement of CMA in ferritin degradation in response to a biological stimulus. These results also may help in better understanding iron dyshomeostasis and mitochondrial dysfunction reported in PD.
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Affiliation(s)
- Som Dev
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India; Department of Biochemistry, All India Institute of Medical Sciences, Kalyani, West Bengal, India, 741245
| | - Somya Asthana
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Pratibha Singh
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Pankaj Seth
- National Brain Research Centre, Manesar, Haryana, 122052, India
| | - Chayanika Banerjee
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Chinmay K Mukhopadhyay
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
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21
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Ru Q, Li Y, Zhang X, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects. Bone Res 2025; 13:27. [PMID: 40000618 PMCID: PMC11861620 DOI: 10.1038/s41413-024-00398-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/23/2024] [Accepted: 12/16/2024] [Indexed: 02/27/2025] Open
Abstract
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xi Zhang
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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22
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Morishima T, Fakruddin M, Kanamori Y, Masuda T, Ogawa A, Wang Y, Schoonenberg VAC, Butter F, Arima Y, Akaike T, Moroishi T, Tomizawa K, Suda T, Wei FY, Takizawa H. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis. SCIENCE ADVANCES 2025; 11:eadu3011. [PMID: 39983002 PMCID: PMC11844735 DOI: 10.1126/sciadv.adu3011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 01/22/2025] [Indexed: 02/23/2025]
Abstract
Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.
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Affiliation(s)
- Tatsuya Morishima
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMS, Kumamoto University, Kumamoto, Japan
| | - Md. Fakruddin
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMS, Kumamoto University, Kumamoto, Japan
| | - Yohei Kanamori
- Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takeshi Masuda
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Akiko Ogawa
- Department of Modomics Biology and Medicine, IDAC, Tohoku University, Sendai, Japan
| | - Yuxin Wang
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | | | - Falk Butter
- Quantitative Proteomics, Institute of Molecular Biology, 55128 Mainz, Germany
| | - Yuichiro Arima
- Laboratory of Developmental Cardiology, IRCMS, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Takaaki Akaike
- Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshiro Moroishi
- Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Kazuhito Tomizawa
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Toshio Suda
- Laboratory of Stem Cell Regulation, IRCMS, Kumamoto University, Kumamoto, Japan
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Fan-Yan Wei
- Department of Modomics Biology and Medicine, IDAC, Tohoku University, Sendai, Japan
| | - Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
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23
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Isasi E, Olivera-Bravo S. Neurovascular unit impairment in iron deficiency anemia. Neuroscience 2025; 567:56-66. [PMID: 39733822 DOI: 10.1016/j.neuroscience.2024.12.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/16/2024] [Accepted: 12/26/2024] [Indexed: 12/31/2024]
Abstract
Iron is one of the crucial elements for CNS development and function and its deficiency (ID) is the most common worldwide nutrient deficit in the world. Iron deficiency anemia (IDA) in pregnant women and infants is a worldwide health problem due to its high prevalence and its irreversible long-lasting effects on brain development. Even with iron supplementation, IDA during pregnancy and/or breastfeeding can result in irreversible cognitive, motor, and behavioral impairments. The neurovascular unit (NVU) plays an important role in iron transport within the CNS as well as in the blood brain-barrier (BBB) formation and maturation, vasculogenesis/angiogenesis, neurovascular coupling and metabolic waste clearance. In animal models of IDA, significant changes have been observed at the capillary level, including alterations in iron transport, vasculogenesis, astrocyte endfeet, and pericytes. Despite these findings, the role of the NVU in IDA remains poorly understood. This review summarizes the potential effects of ID/IDA on brain development, myelination and neuronal function and discusses the role of NVU cells in iron metabolism, BBB, vasculogenesis/angiogenesis, neurovascular coupling and metabolic waste clearance. Furthermore, it emphasizes the need to view the NVU as a whole and as a potential target for ID/IDA. However, it remains unclear to what extent NVU alterations contribute to neuronal dysfunction, myelination abnormalities, and synaptic disturbances described in IDA.
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Affiliation(s)
- Eugenia Isasi
- Unidad Académica de Histología y Embriología, Facultad de Medicina, UdelaR, Montevideo, Uruguay; Departamento de Neurobiología y Neuropatología, IIBCE, MEC, Montevideo, Uruguay
| | - Silvia Olivera-Bravo
- Departamento de Neurobiología y Neuropatología, IIBCE, MEC, Montevideo, Uruguay.
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24
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Li B, Wu F, Xie Z, Kang X, Wang Y, Li W, Hu X. High acid-base tolerance and long storage time lanthanum cerium co-doped carbon quantum dots for Fe 3+ detection. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 327:125403. [PMID: 39515230 DOI: 10.1016/j.saa.2024.125403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 10/19/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
In this paper, lanthanum and cerium co-doped carbon quantum dots (LaCe-CQDs) was firstly synthesized by one step hydrothermal method. The obtained LaCe-CQDs shown sable fluorescence properties with pH values from 3 to 9 and after 4 weeks of storage. The average particle size of LaCe-CQDs, with excitation and emission wavelengths of 350 nm and 446 nm, is 3.27 ± 0.12 nm. Selective analysis of various metal ions revealed the sensitivity of LaCe-CQDs towards Fe3+ ions. Within the 0-60 μM, the fluorescence intensity exhibits a strong linear correlation with the concentration of Fe3+. The limit of detection (LOD) was determined to be 0.753 μM. Additionally, the accuracy of LaCe-CQDs were demonstrated in natural water samples. Therefore, LaCe-CQDs are a promising sensor for Fe3+ detection.
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Affiliation(s)
- Bangxing Li
- College of Science, Chongqing University of Technology, Chongqing 400054, China; The Green Aerotechnics Research Institute of CQJYU, Chongqing 400054, China; Department of Applied Physics, Chongqing Key Laboratory of Soft Condensed Matter Physics and Smart Materials, State Key Laboratory of Power Transmission Equipment & System Security and New Technology, Chongqing University, Chongqing 400044, China; Chongqing Key Laboratory of New Energy Storage Materials and Devices, Chongqing 400054, China.
| | - Fei Wu
- College of Science, Chongqing University of Technology, Chongqing 400054, China.
| | - Zhenjun Xie
- School of Electronic Commerce, Chongqing Business Vocational College, Chongqing 401331, China.
| | - Xing Kang
- College of Science, Chongqing University of Technology, Chongqing 400054, China
| | - Yanghua Wang
- College of Science, Chongqing University of Technology, Chongqing 400054, China
| | - Wei Li
- College of Science, Chongqing University of Technology, Chongqing 400054, China
| | - Xiaolin Hu
- College of Science, Chongqing University of Technology, Chongqing 400054, China
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25
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Wang Z, Wu C, Yin D, Dou K. Ferroptosis: mechanism and role in diabetes-related cardiovascular diseases. Cardiovasc Diabetol 2025; 24:60. [PMID: 39920799 PMCID: PMC11806630 DOI: 10.1186/s12933-025-02614-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 01/24/2025] [Indexed: 02/09/2025] Open
Abstract
Cardiovascular diseases represent the principal cause of death and comorbidity among people with diabetes. Ferroptosis, an iron-dependent non-apoptotic regulated cellular death characterized by lipid peroxidation, is involved in the pathogenesis of diabetic cardiovascular diseases. The susceptibility to ferroptosis in diabetic hearts is possibly related to myocardial iron accumulation, abnormal lipid metabolism and excess oxidative stress under hyperglycemia conditions. Accumulating evidence suggests ferroptosis can be the therapeutic target for diabetic cardiovascular diseases. This review summarizes ferroptosis-related mechanisms in the pathogenesis of diabetic cardiovascular diseases and novel therapeutic choices targeting ferroptosis-related pathways. Further study on ferroptosis-mediated cardiac injury can enhance our understanding of the pathophysiology of diabetic cardiovascular diseases and provide more potential therapeutic choices.
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Affiliation(s)
- Ziyi Wang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Cardiometabolic Medicine Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chao Wu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Cardiometabolic Medicine Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dong Yin
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Cardiometabolic Medicine Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Kefei Dou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- Cardiometabolic Medicine Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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26
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Xie X, Chang L, Zhu X, Gong F, Che L, Zhang R, Wang L, Gong C, Fang C, Yao C, Hu D, Zhao W, Zhou Y, Zhu S. Rubiadin Mediates the Upregulation of Hepatic Hepcidin and Alleviates Iron Overload via BMP6/SMAD1/5/9-Signaling Pathway. Int J Mol Sci 2025; 26:1385. [PMID: 39941155 PMCID: PMC11818739 DOI: 10.3390/ijms26031385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025] Open
Abstract
Iron overload disease is characterized by the excessive accumulation of iron in the body. To better alleviate iron overload, there is an urgent need for safe and effective small molecule compounds. Rubiadin, the active ingredient derived from the Chinese herb Prismatomeris tetrandra, possesses notable anti-inflammatory and hepatoprotective properties. Nevertheless, its impact on iron metabolism remains largely unexplored. To determine the role of rubiadin on iron metabolism, Western blot analysis, real-time PCR analysis, and the measurement of serum iron were performed. Herein, we discovered that rubiadin significantly downregulated the expression of transferrin receptor 1, ferroportin 1, and ferritin light chain in ferric-ammonium-citrate-treated or -untreated HepG2 cells. Moreover, intraperitoneal administration of rubiadin remarkably decreased serum iron and duodenal iron content and upregulated expression of hepcidin mRNA in the livers of high-iron-fed mice. Mechanistically, bone morphogenetic protein 6 (BMP6) inhibitor LDN-193189 completely reversed the hepcidin upregulation and suppressor of mother against decapentaplegic 1/5/9 (SMAD1/5/9) phosphorylation induced by rubiadin. These results suggested that rubiadin increased hepcidin expression through the BMP6/SMAD1/5/9-signaling pathway. Collectively, our findings uncover a crucial mechanism through which rubiadin modulates iron metabolism and highlight it as a potential natural compound for alleviating iron-overload-related diseases.
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Affiliation(s)
- Xueting Xie
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Linyue Chang
- Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (L.C.); (F.G.); (R.Z.); (W.Z.)
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Xinyue Zhu
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Fengbei Gong
- Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (L.C.); (F.G.); (R.Z.); (W.Z.)
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Linlin Che
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Rujun Zhang
- Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (L.C.); (F.G.); (R.Z.); (W.Z.)
| | - Lixin Wang
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chenyuan Gong
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cheng Fang
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chao Yao
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Dan Hu
- School of Acupuncture, Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, 1200 CaiLun Rd., Shanghai 201203, China;
| | - Weimin Zhao
- Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; (L.C.); (F.G.); (R.Z.); (W.Z.)
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Yufu Zhou
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shiguo Zhu
- Department of Immunology and Pathogenic Biology, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (X.X.); (X.Z.); (L.C.); (L.W.); (C.G.); (C.F.); (C.Y.)
- Center for Traditional Chinese Medicine and Immunology Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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27
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Qian X, Zhou Q, Ouyang Y, Wu X, Sun X, Wang S, Duan Y, Hu Z, Hou Y, Wang Z, Chen X, Wang KL, Shen Y, Dong B, Lin Y, Wen T, Tian Q, Guo Z, Li M, Xiao L, Wu Q, Meng Y, Liu G, Ying H, Zhou Y, Zhang W, Duan S, Bai X, Liu T, Zhan P, Lu Z, Xu D. Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner. Proc Natl Acad Sci U S A 2025; 122:e2412473122. [PMID: 39888917 PMCID: PMC11804496 DOI: 10.1073/pnas.2412473122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 01/02/2025] [Indexed: 02/02/2025] Open
Abstract
Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.
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Affiliation(s)
- Xu Qian
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou310022, China
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Qimin Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai200011, China
| | - Yuan Ouyang
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai200125, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Xiaohong Wu
- National Health Commission (NHC) Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Harbin, Heilongjiang150081, China
| | - Xue Sun
- Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang150081, China
| | - Shuo Wang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong250012, China
| | - Yuran Duan
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Zhiqiang Hu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Yueru Hou
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Zheng Wang
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Xiaohan Chen
- Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang150081, China
| | | | - Yuli Shen
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Bofei Dong
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Yanni Lin
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Ting Wen
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Qi Tian
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Zhanpeng Guo
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Min Li
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Liwei Xiao
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Qingang Wu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Ying Meng
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Guijun Liu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Hangjie Ying
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou310022, China
| | - Yahui Zhou
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou310022, China
| | - Wuchang Zhang
- Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai200125, China
- National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Shengzhong Duan
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou310000, China
| | - Xueli Bai
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
| | - Tong Liu
- Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang150081, China
- National Health Commission (NHC) Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, Heilongjiang150081, China
| | - Peng Zhan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong250012, China
| | - Zhimin Lu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
| | - Daqian Xu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang310029, China
- Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, Zhejiang310029, China
- National Health Commission (NHC) Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, Heilongjiang150081, China
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28
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Gil J, Kim D, Choi S, Bae ON. Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway. Toxicol Appl Pharmacol 2025; 495:117233. [PMID: 39842614 DOI: 10.1016/j.taap.2025.117233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/12/2025] [Accepted: 01/15/2025] [Indexed: 01/24/2025]
Abstract
Cadmium (Cd2+) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd2+ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd2+ on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd2+ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd2+ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd2+ exposure. Cd2+ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd2+ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd2+ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.
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Affiliation(s)
- Junkyung Gil
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
| | - Donghyun Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
| | - Sungbin Choi
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
| | - Ok-Nam Bae
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
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29
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Cornelis MC, Fazlollahi A, Bennett DA, Schneider JA, Ayton S. Genetic Markers of Postmortem Brain Iron. J Neurochem 2025; 169:e16309. [PMID: 39918201 PMCID: PMC11804167 DOI: 10.1111/jnc.16309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/26/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025]
Abstract
Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome-wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed the first GWAS of inductively coupled plasma mass spectrometry measures of postmortem brain Fe from 635 Rush Memory and Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated with Fe in at least one of four brain regions were measured (p < 5 × 10-8). Promising SNPs (p < 5 × 10-6) were followed up for replication in published GWAS of blood, spleen, and brain imaging Fe traits and mapped to candidate genes for targeted cortical transcriptomic and epigenetic analysis of postmortem Fe in MAP. Results for SNPs previously associated with other Fe traits were also examined. Ninety-eight SNPs associated with postmortem brain Fe were at least nominally (p < 0.05) associated with one or more related Fe traits. Most novel loci identified had no direct links to Fe regulatory pathways but rather endoplasmic reticulum-Golgi trafficking (SORL1, SORCS2, MARCH1, CLTC), heparan sulfate (HS3ST4, HS3ST1), and coenzyme A (SLC5A6, PANK3); supported by nearest gene function and omic analyses. We replicated (p < 0.05) several previously published Fe loci mapping to candidate genes in cellular and systemic Fe regulation. Finally, novel loci (BMAL, COQ5, SLC25A11) and replication of prior loci (PINK1, PPIF, LONP1) lend support to the role of circadian rhythms and mitochondria function in Fe regulation more generally. In summary, we provide support for novel loci linked to pathways that may have greater relevance to brain Fe accumulation; some of which are implicated in neurodegeneration. However, replication of a subset of prior loci for blood Fe suggests that genetic determinants or biological pathways underlying Fe accumulation in the brain are not completely distinct from those of Fe circulating in the periphery.
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Affiliation(s)
- Marilyn C. Cornelis
- Department of Preventive MedicineNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Amir Fazlollahi
- Department of Radiology, Royal Melbourne HospitalUniversity of MelbourneMelbourneVictoriaAustralia
- Queensland Brain InstituteThe University of QueenslandBrisbaneQueenslandAustralia
| | | | | | - Scott Ayton
- The Florey Institute of Neuroscience and Mental HealthMelbourneVictoriaAustralia
- Florey Department of Neuroscience and Mental HealthThe University of MelbourneMelbourneVictoriaAustralia
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30
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Cancado RD, Leite LAC, Muñoz M. Defining Global Thresholds for Serum Ferritin: A Challenging Mission in Establishing the Iron Deficiency Diagnosis in This Era of Striving for Health Equity. Diagnostics (Basel) 2025; 15:289. [PMID: 39941219 PMCID: PMC11817370 DOI: 10.3390/diagnostics15030289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 02/16/2025] Open
Abstract
Iron deficiency (ID) is a critical public health issue globally and the most prevalent cause of anemia. Iron deficiency anemia (IDA) affects approximately 1.2 billion individuals worldwide, and it is estimated that non-anemic iron deficiency (NAID) is at least twice as common as IDA. Yet, there is still uncertainty about how to diagnose it in clinical practice. The serum ferritin (SF) threshold of <15 ng/mL proposed by the World Health Organization (WHO) has been questioned over the last decade. The current SF thresholds are inappropriately low, and, therefore, a large portion of the population at the most significant risk of ID remain undiagnosed and untreated. The correlation between SF, hepcidin, and the physiological upregulation of iron absorption in healthy adults suggests that SF of <50 ng/mL indicates a more precise threshold for diagnosing ID in adults. Therefore, adopting the SF threshold <50 ng/mL would break up the perpetuation of an inequitable cycle of disadvantage for ID individuals, especially among women.
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Affiliation(s)
- Rodolfo Delfini Cancado
- Department of Hematology, Faculdade de Ciências Médicas da Santa Casa de Sao Paulo, Sao Paulo 01224-001, Brazil;
- Department of Oncology, Faculdade de Ciências Médicas da Santa Casa de Sao Paulo, Sao Paulo 01224-001, Brazil
- Hospital Samaritano de Sao Paulo, Sao Paulo 01232-010, Brazil
| | - Lauro Augusto Caetano Leite
- Department of Hematology, Faculdade de Ciências Médicas da Santa Casa de Sao Paulo, Sao Paulo 01224-001, Brazil;
- Department of Oncology, Faculdade de Ciências Médicas da Santa Casa de Sao Paulo, Sao Paulo 01224-001, Brazil
- Hospital Samaritano de Sao Paulo, Sao Paulo 01232-010, Brazil
| | - Manuel Muñoz
- Peri-Operative Transfusion Medicine, School of Medicine, 29010 Malaga, Spain;
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31
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Angelucci E. How I manage iron overload in the hematopoietic cell transplantation setting. Blood 2025; 145:372-382. [PMID: 38728389 DOI: 10.1182/blood.2023022500] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/12/2024] Open
Abstract
ABSTRACT The success of hematopoietic transplantation for hemoglobinopathies and hematological malignancies has been accompanied by the new challenge of how to identify, risk stratify, and treat iron overload and toxicity before and after transplantation. Substantial progress has been made in our understanding of iron metabolism and the pathophysiology of iron overload, making us aware that not only the total amount of iron in the body is important but also the effect of toxic iron species and duration of exposure are equally relevant. Challenges still remain in how to assess cellular and tissue damage and define the mechanism that may detrimentally affect the outcome of hematopoietic transplantation. In this article, I discuss the impact of iron toxicity in relation to the different phases of hematopoietic transplantation, before, during, and after, for both malignant and nonmalignant diseases. Different clinical scenarios and possibilities for therapeutic intervention are also outlined and discussed.
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Affiliation(s)
- Emanuele Angelucci
- Hematology and Cellular Therapy, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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32
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Liu C, Liu Z, Dong Z, Liu S, Kan H, Zhang S. Multifaceted interplays between the essential players and lipid peroxidation in ferroptosis. J Genet Genomics 2025:S1673-8527(25)00024-4. [PMID: 39862922 DOI: 10.1016/j.jgg.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 01/17/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025]
Abstract
Ferroptosis, a type of programmed cell death, represents a distinct paradigm in cell biology. It is characterized by the iron-dependent accumulation of reactive oxygen species, which induce lipid peroxidation (LPO), and is orchestrated by the interplay between iron, lipid peroxides, and glutathione. In this review, we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis, including iron intake and export as well as ferritinophagy, and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases, especially P450 oxidoreductases, in modulating LPO. We summarize how various types of fatty acids (FAs), including saturated, monounsaturated, and polyunsaturated FAs, differentially influence ferroptosis when incorporated into phospholipids. Furthermore, we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis, shedding light on therapeutic avenues for ferroptosis-associated diseases.
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Affiliation(s)
- Conghe Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Zhihao Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Zheng Dong
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Sijin Liu
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Haidong Kan
- School of Public Health, Key Lab of Public Health Safety of the Ministry of Education and NHC Key Lab of Health Technology Assessment, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China
| | - Shuping Zhang
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
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33
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Szymulewska-Konopko K, Reszeć-Giełażyn J, Małeczek M. Ferritin as an Effective Prognostic Factor and Potential Cancer Biomarker. Curr Issues Mol Biol 2025; 47:60. [PMID: 39852175 PMCID: PMC11763953 DOI: 10.3390/cimb47010060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/05/2025] [Accepted: 01/13/2025] [Indexed: 01/26/2025] Open
Abstract
Ferritin is found in all cells of the body, serving as a reservoir of iron and protecting against damage to the molecules that make up cellular structures. It has emerged as a biomarker not only for iron-related disorders but also for inflammatory diseases and conditions in which inflammation plays a key role, including cancer, neurodegeneration, and infection. Oxidative stress, which can cause cellular damage, is induced by reactive oxygen species generated during the Fenton reaction, activating signaling pathways associated with tumor growth and proliferation. This review primarily emphasizes basic studies on the identification and function of ferritin, its essential role in iron metabolism, its involvement in inflammatory diseases, and its potential as an important prognostic factor and biomarker for cancer detection.
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Affiliation(s)
| | - Joanna Reszeć-Giełażyn
- Department of Medical Pathomorphology, Medical University of Bialystok, 15-089 Białystok, Poland; (K.S.-K.); (M.M.)
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34
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Rayêe D, Hwang DW, Chang WK, Karp IN, Zhao Y, Bowman T, Lachke SA, Singer RH, Eliscovich C, Cvekl A. Identification and classification of abundant RNA-binding proteins in the mouse lens and interactions of Carhsp1, Igf2bp1/ZBP1, and Ybx1 with crystallin and β-actin mRNAs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.10.632466. [PMID: 39829794 PMCID: PMC11741318 DOI: 10.1101/2025.01.10.632466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
RNA-binding proteins (RBPs) are critical regulators of mRNAs controlling all processes such as RNA transcription, transport, localization, translation, mRNA:ncRNA interactions, and decay. Cellular differentiation is driven by tissue-specific and/or tissue-preferred expression of proteins needed for the optimal function of mature cells, tissues and organs. Lens fiber cell differentiation is marked by high levels of expression of crystallin genes encoding critical proteins for lens transparency and light refraction. Herein we performed proteomic and transcriptomic analyses of RBPs in differentiating mouse lenses to identify the most abundant RBPs and establish dynamic changes of their expression in differentiating lens. Expression analyses include highly abundant RBPs, including Carhsp1, Igf2bp1/ZBP1, Ybx1, Pabpc1, Ddx39, and Rbm38. Binding sites of Carhsp1, Ybx1, and Igf2bp1/ZBP1 were predicted in various crystallin and β-actin mRNAs. Immunoprecipitations using antibodies against Carhsp1, Igf2bp1/ZBP1, and Ybx1 confirmed their interactions with αA-, αB-, and γA-crystallin mRNAs. A combination of single molecule RNA FISH (smFISH) and immunofluorescence was used to probe in vivo interactions of these RBPs with αA-, αB-crystallin, and β-actin mRNAs in cytoplasm and nucleoplasm of cultured mouse lens epithelial cells. Together, these results open new avenues to perform comprehensive genetic, cell, and molecular biology studies of individual RBPs in the lens.
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35
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Imam M, Ji J, Zhang Z, Yan S. Targeting the initiator to activate both ferroptosis and cuproptosis for breast cancer treatment: progress and possibility for clinical application. Front Pharmacol 2025; 15:1493188. [PMID: 39867656 PMCID: PMC11757020 DOI: 10.3389/fphar.2024.1493188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 11/12/2024] [Indexed: 01/28/2025] Open
Abstract
Breast cancer is the most commonly diagnosed cancer worldwide. Metal metabolism is pivotal for regulating cell fate and drug sensitivity in breast cancer. Iron and copper are essential metal ions critical for maintaining cellular function. The accumulation of iron and copper ions triggers distinct cell death pathways, known as ferroptosis and cuproptosis, respectively. Ferroptosis is characterized by iron-dependent lipid peroxidation, while cuproptosis involves copper-induced oxidative stress. They are increasingly recognized as promising targets for the development of anticancer drugs. Recently, compelling evidence demonstrated that the interplay between ferroptosis and cuproptosis plays a crucial role in regulating breast cancer progression. This review elucidates the converging pathways of ferroptosis and cuproptosis in breast cancer. Moreover, we examined the value of genes associated with ferroptosis and cuproptosis in the clinical diagnosis and treatment of breast cancer, mainly outlining the potential for a co-targeting approach. Lastly, we delve into the current challenges and limitations of this strategy. In general, this review offers an overview of the interaction between ferroptosis and cuproptosis in breast cancer, offering valuable perspectives for further research and clinical treatment.
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Affiliation(s)
| | | | | | - Shunchao Yan
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
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36
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Roe K. Preeclampsia and eclampsia: the role of hemolytic protozoan iron. Adv Clin Chem 2025; 125:169-194. [PMID: 39988406 DOI: 10.1016/bs.acc.2024.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Organisms as well as pathogens require several transition metals including iron, copper, zinc, manganese, nickel and cobalt, for genetic replication and other cellular functions. Of these, iron is vital and plays a key role in DNA replication, transcription, synthesis of cofactors and other essential enzymes. During infection, iron deprivation, particularly sequestration thereof, represents a unique response against pathogen attack. The host sequesters ferrous (Fe2+) and ferric (Fe3+) iron via lactoferrin binding at mucosal surfaces, transferrin in blood and tissue and ferritin in blood and cytoplasm. Despite this protective mechanism, pathogens can be resilient in obtaining iron. For example, hemolytic protozoan parasites can obtain iron from heme by rupturing red blood cells. Furthermore, earlier pathogens, driven from active to inactive infections by iron deprivation, could now acquire sufficient iron to enable reactivation resulting in chronic inflammation, oxidative stress to organs and/or circulatory hypertension potentially leading to death. This review discusses the impact of hemolytic protozoan parasite infection in reactivation of latent iron-deprived pathogen infections thus explaining two puzzling pregnancy disorders, pre-eclampsia (PE) and eclampsia. The unknown causations of both disorders have created centuries of confusion and killed millions of women worldwide. Furthermore, reduction-oxidation reactions with iron promote additional oxidative stress damage to vital organs, particularly the kidneys, a common symptom in PE and eclampsia.
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Affiliation(s)
- Kevin Roe
- United States Patent and Trademark Office, San Jose, California, United States.
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Wu W, Li Y, Liu Q, Liu T, Zhao Y, Shao H, Ren P, Tang Y, Feng J, Wang Y, Sun G, Liu H, Bai Y, Chen F. Dual-Targeted Drug Delivery to Myeloid Leukemia Cells via Complement- and Transferrin-Based Protein Corona. NANO LETTERS 2025; 25:147-156. [PMID: 39694635 DOI: 10.1021/acs.nanolett.4c04429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Although traditionally regarded as an impediment, the protein corona can facilitate the advancement of targeted drug delivery systems. This study presents an innovative approach for targeting acute myeloid leukemia (AML) using nanoparticles with agglutinated protein (NAPs). Agglutinated transferrin and C3b in NAPs selectively bind to CD71 and CD11b, receptors that are overexpressed on myeloid leukemic cells compared to nonmalignant cells. In vitro, NAPs achieved a 73.9% doxorubicin (DOX) uptake in leukemic cells, compared to 6.19% for the free drug, while significantly reducing off-target accumulation in normal cells from 42.9% to 5.76%. In vivo, the distribution of NAPs correlated to the organ infiltration pattern of leukemic cells. NAPs demonstrated antileukemic activity in both in vitro and in vivo NSG mouse models, inducing cell death via apoptosis and ferroptosis. In conclusion, NAP-mediated targeted drug delivery represents a promising therapeutic strategy for AML, enhancing treatment efficacy and minimizing off-target effects.
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Affiliation(s)
- Wen Wu
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Yuanyuan Li
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Qihui Liu
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Tao Liu
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Yanan Zhao
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Hui Shao
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Ping Ren
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 130033, P. R. China
| | - Yueyang Tang
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Jiayi Feng
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Yihan Wang
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Guodong Sun
- Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, P. R. China
| | - Haiyan Liu
- Key Laboratory of Pathobiology Ministry of Education, Department of Anatomy, College of Basic Medical Sciences, Jilin University, Changchun 130021, P. R. China
| | - Yuansong Bai
- Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
| | - Fangfang Chen
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Key Laboratory of Pathobiology, Ministry of Education, Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P. R. China
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Wang Y, He Z, Dong X, Yao Y, Chen Q, Shi Y, Deng Y, Zhang Q, Yu L, Wang C. Regulation and therapy: the role of ferroptosis in DLBCL. Front Pharmacol 2025; 15:1458412. [PMID: 39834804 PMCID: PMC11743434 DOI: 10.3389/fphar.2024.1458412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell non-Hodgkin's lymphoma (NHL), up to 30%-40% of patients will relapse and 10%-15% of patients have primary refractory disease, so exploring new treatment options is necessary. Ferroptosis is a non-apoptotic cell death mode discovered in recent years. Its occurrence pathway plays an essential impact on the therapeutic effect of tumors. Numerous studies have shown that modulating critical factors in the ferroptosis pathway can influence the growth of tumor cells in hematological malignancies including DLBCL. This review highlights recent advances in ferroptosis-related genes (FRGs), including STAT3, Nrf2, and ZEB1, and focuses on the clinical potential of ferroptosis inducers such as IKE, α-KG, DMF, and APR-246, which are currently being explored in clinical studies for their therapeutic effects in DLBCL. Correlational studies provide a novel idea for the research and treatment of ferroptosis in DLBCL and other hematological malignancies and lay a solid foundation for future studies.
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Affiliation(s)
- Yifan Wang
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Zhengmei He
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Xinyu Dong
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Huaian Clinical College of Xuzhou Medical University, Huai’an, China
| | - Yiming Yao
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Huaian Clinical College of Xuzhou Medical University, Huai’an, China
| | - Qiuni Chen
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yuye Shi
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yuan Deng
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Quane Zhang
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Liang Yu
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Huaian Clinical College of Xuzhou Medical University, Huai’an, China
| | - Chunling Wang
- Department of Hematology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an, China
- Northern Jiangsu Institute of Clinical Medicine, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Huaian Clinical College of Xuzhou Medical University, Huai’an, China
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Alves F, Lane D, Nguyen TPM, Bush AI, Ayton S. In defence of ferroptosis. Signal Transduct Target Ther 2025; 10:2. [PMID: 39746918 PMCID: PMC11696223 DOI: 10.1038/s41392-024-02088-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/10/2024] [Accepted: 11/29/2024] [Indexed: 01/04/2025] Open
Abstract
Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.
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Affiliation(s)
- Francesca Alves
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Darius Lane
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia
| | | | - Ashley I Bush
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
| | - Scott Ayton
- The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
- Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
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Ahmed AKR, Gajendhiran R, Mithra S, Majeed SA, Hameed ASS, Paulpandiyan R, Maniyammai S, Senthil Andavan GT, NizamMohideen M, Rahiman AK. Salicylidene-based dual-responsive 'turn on' fluorometric chemosensors for the selective detection of Zn 2+, Al 3+ and F - ions: theoretical investigation and applications in the live cell imaging of zebrafish larvae and molecular logic gate operation. J Mater Chem B 2025; 13:622-641. [PMID: 39601190 DOI: 10.1039/d4tb01356e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Four salicylidene-based dual-responsive chemosensors 1,5-bis(5-bromosalicylaldehyde)carbohydrazone (R1), 1,5-bis(5-bromosalicylaldehyde)thiocarbohydrazone (R2), 1,5-bis(3-ethoxysalicylaldehyde)carbohydrazone (R3) and 1,5-bis(3-ethoxysalicylaldehyde)thiocarbohydrazone (R4) were synthesized and characterized. The molecular structures of R1 and R3 were confirmed by single crystal X-ray diffraction technique, which crystallized in the orthorhombic Pbcn and monoclinic P21/n space groups, respectively. The chemosensor molecules were investigated for their recognition properties against the selected cations (K+, Ca2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, Fe3+ and Al3+) and anions (F-, Cl-, Br-, I-, HSO4-, H2PO4-, ClO4-, N3- and NO3-) by colorimetry, absorption spectroscopy, fluorescence spectroscopy, 1H NMR spectroscopy and theoretical studies. The sensor molecules showed colorimetric responses for the Co2+, Ni2+, Cu2+ and Fe3+ cations and the F- anion. Interestingly, the Zn2+ and Al3+ cations showed only the 'turn on' fluorometric response, whereas the F- anion showed both colorimetric and fluorometric responses. The binding constants were determined using the Benesi-Hildebrand (B-H) equation from the fluorescence titrations and found to be higher for R3 towards the Al3+ cation (2.03 × 106 M-1) with a low limit of detection (1.79 μM) and for R4 towards the F- anion (5.13 × 105 M-1) with a low limit of detection (5.23 μM). The chemosensors established 1 : 2 and 1 : 1 binding stoichiometries with the sensed cations and anion, respectively, as confirmed by Job's plots. The computational studies show a lower band gap of HOMO-LUMO when the chemosensors bind with the sensed inorganic ions compared to the free chemosensors. Furthermore, the observed fluorescent behaviour of the Zn2+ and Al3+ cations have motivated us to investigate the practical applications in the live cell-imaging of zebrafish larvae as well as in the development of a molecular logic gate.
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Affiliation(s)
- Abbas Khaja Raees Ahmed
- Post-Graduate and Research Department of Chemistry, The New College, University of Madras, Chennai - 600 014, India.
| | - Ramalingam Gajendhiran
- Post-Graduate and Research Department of Chemistry, The New College, University of Madras, Chennai - 600 014, India.
| | - Sivaraj Mithra
- Department of Zoology and Aquatic Animal Health Laboratory, C. Abdul Hakeem College, Melvisharam - 632 509, India
| | - Seepoo Abdul Majeed
- Department of Zoology and Aquatic Animal Health Laboratory, C. Abdul Hakeem College, Melvisharam - 632 509, India
| | - Azeez Sait Sahul Hameed
- Department of Zoology and Aquatic Animal Health Laboratory, C. Abdul Hakeem College, Melvisharam - 632 509, India
| | | | - Subbaiah Maniyammai
- Department of Chemistry, SRM Institute of Science and Technology, Kattankulathur, Chennai - 603 203, India
| | | | - MohamedHanifa NizamMohideen
- Post-Graduate and Research Department of Physics, The New College, University of Madras, Chennai - 600 014, India
| | - Aziz Kalilur Rahiman
- Post-Graduate and Research Department of Chemistry, The New College, University of Madras, Chennai - 600 014, India.
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Zhang JX, Lan MF, Shang JZ, Lai XL, Li LS, Duan TT, Xu RH, Chen KL, Duan X. DMT1 Maintains Iron Homeostasis to Regulate Mitochondrial Function in Porcine Oocytes. J Cell Physiol 2025; 240:e31494. [PMID: 39639679 DOI: 10.1002/jcp.31494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/29/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024]
Abstract
Iron plays critical roles in many cellular functions, including energy production, metabolism, and cell proliferation. However, the role of iron in maintaining oocyte quality remains unclear. In this study, DMT1 was identified as a key iron transporter during porcine oocyte maturation. The results demonstrated that iron deficiency in porcine oocyte led to aberrant meiotic progression, accompanied by increased gene expression of DMT1. Inhibition of DMT1 resulted in the failure of cumulus cell expansion and oocyte maturation, along by the abnormal actin and microtubule assembly. Furthermore, loss of DMT1 function caused disruption in mitochondrial function and dynamics, resulting in oxidative stress and Ca2+ dyshomeostasis. Additionally, the absence of DMT1 function activated PINK1/Parkin-dependent mitophagy in porcine oocyte. These findings suggested that DMT1 played a crucial role in safeguarding oocyte quality by protecting against iron-deficiency-induced mitochondrial dysfunction and autophagy. This study provided compelling evidence that DMT1 and iron homeostasis were crucial for maintaining the capacity of porcine oocyte maturation. Moreover, the results hinted at the potential of DMT1 as a novel therapeutic target for treating iron deficiency-related female reproductive disorders.
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Affiliation(s)
- Jin-Xin Zhang
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
| | - Meng-Fan Lan
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
| | - Jian-Zhou Shang
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
| | - Xin-Le Lai
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
| | - Li-Shu Li
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
| | - Tong-Tong Duan
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
| | - Ru-Hai Xu
- Key Laboratory of Animal Genetics and Breeding of Zhejiang Province, Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
| | - Kun-Lin Chen
- Key Laboratory of Crop and Animal Integrated Farming, Ministry of Agriculture, Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu, China
| | - Xing Duan
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou, Zhejiang, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
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Yankuzo HM, Sulaiman I, Muhammad SA, Raji AA, Uthman YA, Imam MU. Brown rice attenuates iron-induced Parkinson's disease phenotypes in male wild-type drosophila: insights into antioxidant and iron metabolism modulation. Appl Physiol Nutr Metab 2025; 50:1-13. [PMID: 39588846 DOI: 10.1139/apnm-2024-0110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
Parkinson's disease (PD) is a progressive movement disorder associated with brain iron (Fe) accumulation and free radicals. Brown rice (BR) is antioxidant-rich and has been shown to ameliorate oxidative stress-induced damage. The aim of this study was to investigate the effects of BR compared to white rice (WR) on Fe-induced PD in a fruit fly model. Three-day-old male adult flies were divided into two groups: one on a normal diet and the other on Fe-diet (1 mmol/L) for 10 days to induce PD. After 10 days, the Fe-fed flies were redistributed into four groups: one on normal diet (Fe group), while the others were treated with BR (Fe + BR group), WR (Fe + WR group), or L-3,4-dihydroxyphenylalanine (L-dopa) (Fe + L-dopa group) for 5 days. Similarly, the flies initially on a normal diet were separated into four groups: one on normal diet (Control group), while the others were treated with BR (BR group), WR (WR group), or L-dopa (L-dopa group) for 5 days. Finally, Fe levels, dopamine, malonaldehyde (MDA), and antioxidant enzymes were measured, and the mRNA levels of antioxidant and Fe metabolism genes were assessed. BR significantly improved motor and cognitive functions, decreased fly head MDA and Fe levels, and increased antioxidant enzyme levels in comparison to the Fe and WR groups. Similarly, BR upregulated the mRNA levels of antioxidant genes: catalase, GPx, Nrf2, and DJ-1. The results suggest that BR could potentially reduce morbidities associated with PD possibly due to its bioactive compounds compared to WR.
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Affiliation(s)
- Hassan Muhammad Yankuzo
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Usmanu Danfodiyo University Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria
| | - Ismail Sulaiman
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria
- Department of Biochemistry and Molecular Biology, Faculty of Chemical and Life Sciences, Usmanu Danfodiyo University Sokoto, Nigeria
| | - Suleiman Alhaji Muhammad
- Department of Biochemistry and Molecular Biology, Faculty of Chemical and Life Sciences, Usmanu Danfodiyo University Sokoto, Nigeria
| | - Abdullahi Abdullahi Raji
- Department of Veterinary Pathology, Faculty of Veterinary Medicine, Usmanu Danfodiyo University Sokoto, Nigeria
| | - Yaaqub Abiodun Uthman
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria
- Department of Physiology, Faculty of Basic Medical Sciences, Usmanu Danfodiyo University Sokoto, Nigeria
| | - Mustapha Umar Imam
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, Usmanu Danfodiyo University Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University Sokoto, Nigeria
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Sato R, Koziolek MJ, von Haehling S. Translating evidence into practice: Managing electrolyte imbalances and iron deficiency in heart failure. Eur J Intern Med 2025; 131:15-26. [PMID: 39521682 DOI: 10.1016/j.ejim.2024.10.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/23/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024]
Abstract
Mineral abnormalities are a common complication of heart failure (HF). In particular, dyskalaemia, hyponatraemia, and hypomagnesaemia are prevalent, with hypo- and hyperkalaemia observed in over 40 % of HF patients, hyponatraemia in 18-27 %, hypomagnesaemia in 7-52 %, and phosphate imbalance in 13 %. These abnormalities serve as indicators of the severity of HF and are strongly associated with an increased risk of morbidity and mortality. The neurohumoral activation, including the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and vasopressin, HF medications such as diuretics and RAAS inhibitors, amd concomitant diseases such as chronic kidney disease, can disrupt mineral homeostasis. Iron deficiency (ID) is another of the most common mineral abnormalities, affecting up to 60 % of HF patients. ID is significantly associated with adverse clinical outcomes such as reduced quality of life and exercise capacity, HF re-hospitalization, and all-cause mortality. Various pathways contribute to the development of ID in HF, including reduced iron intake due to anorexia, increased hepcidin levels associated with chronic inflammation and hepatic congestion, and occult gastrointestinal bleeding due to the concomitant use of antithrombotic agents. The efficacy of iron replacement therapy has been demonstrated in clinical trials, particularly in heart failure with reduced ejection fraction (HFrEF), whilst more recently, it has also been shown to improve exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). This review focuses on potassium and phosphate abnormalities, hyponatraemia, hypomagnesaemia, and ID in HF, providing a comprehensive overview of the mechanisms, clinical significance, and intervention strategies with the latest findings.
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Affiliation(s)
- Ryosuke Sato
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Lower Saxony, Germany
| | - Michael J Koziolek
- DZHK (German Center for Cardiovascular Research), Partner Site Lower Saxony, Germany; Department of Nephrology and Rheumatology, University Medical Centre, Göttingen, Germany
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Lower Saxony, Germany.
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Arosio P, Cairo G, Bou-Abdallah F. A Brief History of Ferritin, an Ancient and Versatile Protein. Int J Mol Sci 2024; 26:206. [PMID: 39796064 PMCID: PMC11719527 DOI: 10.3390/ijms26010206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/13/2025] Open
Abstract
Ferritin, a highly conserved iron storage protein, is among the earliest proteins that have been purified, named, and characterized due to its unique properties that continue to captivate researchers. Ferritin is composed of 24 subunits that form an almost spherical shell delimiting a cavity where thousands of iron atoms can be stored in a nontoxic ferric form, thereby preventing cytosolic iron from catalyzing oxidative stress. Mitochondrial and extracellular ferritin have also been described and characterized, with the latter being associated with several signaling functions. In addition, serum ferritin serves as a reliable indicator of both iron stores and inflammatory conditions. First identified and purified through crystallization in 1937, ferritin has since drawn significant attention for its critical role in iron metabolism and regulation. Its unique structural features have recently been exploited for many diverse biological and technological applications. To date, more than 40,000 publications have explored this remarkable protein. Here, we present a historical overview, tracing its journey from discovery to current applications and highlighting the evolution of biochemical techniques developed for its structure-function characterization over the past eight decades.
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Affiliation(s)
- Paolo Arosio
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
| | - Gaetano Cairo
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy;
| | - Fadi Bou-Abdallah
- Department of Chemistry, State University of New York at Potsdam, Potsdam, NY 13676, USA;
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Zhang C, Cha R, Long K, Liu Y, Dong Y, Zhang Y, Wang X, Jiang X. Functionalized Iron Oxide Nanoparticles for Both Dual-Modal Imaging and Erythropoiesis. ACS APPLIED MATERIALS & INTERFACES 2024; 16:68905-68917. [PMID: 39656520 DOI: 10.1021/acsami.4c15206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Cancer-related anemia (CRA), a complication of cancer, is considered the primary cause of high mortality for cancer patients. Safe and effective theranostics are desirable for realizing the high diagnostic accuracy of tumors and ameliorating CRA in the clinic. However, the available theranostics do not support dual-modal imaging and the amelioration of CRA at the same time. In this study, we synthesized functionalized iron oxide nanoparticles (Fe3O4 NPs) modified with protoporphyrin IX (PPIX) and folic acid (FA) by a one-step modification strategy (Fe3O4@NH-PPIX&FA NPs) or a step-by-step strategy (Fe3O4@NH-PPIX-FA NPs), aiming at both magnetic resonance imaging/fluorescence imaging (MRI/FI) and erythropoiesis. Fe3O4@NH-PPIX-FA NPs displayed better ability of MRI/FI than Fe3O4@NH-PPIX&FA NPs and had an efficient tumor targeting of 45 min after tail vein injection owing to the reduction of the steric effect and extension of FA groups. Fe3O4@NH-PPIX-FA NPs exhibited satisfactory erythropoiesis with up to 20% elevation of red blood cell (RBC) counts and hemoglobin concentrations in mice with CRA, which provided a safe alternative to RBC transfusions, especially for patients needing recurrent RBC transfusions. With excellent performance in both dual-modal imaging and erythropoiesis, Fe3O4@NH-PPIX-FA NPs could be a powerful tool for the theranostics of cancer patients with anemia.
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Affiliation(s)
- Chunliang Zhang
- Laboratory of Theoretical and Computational Nanoscience, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Zhongguancun Beiyitiao, Haidian District, Beijing 100190, P. R. China
- The Ninth Medical Center of PLA General Hospital, No. 9 Anxiang Beili, Chaoyang District, Beijing 100101, P. R. China
| | - Ruitao Cha
- Laboratory of Theoretical and Computational Nanoscience, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Zhongguancun Beiyitiao, Haidian District, Beijing 100190, P. R. China
- NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, National Institutes for Food and Drug Control, No. 2 Tiantan Xi Li, Dongcheng District, Beijing 100050, P. R. China
| | - Keying Long
- Laboratory of Theoretical and Computational Nanoscience, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Zhongguancun Beiyitiao, Haidian District, Beijing 100190, P. R. China
| | - Yang Liu
- Laboratory of Theoretical and Computational Nanoscience, CAS Center for Excellence in Nanoscience, National Center for NanoScience and Technology, No. 11 Zhongguancun Beiyitiao, Haidian District, Beijing 100190, P. R. China
| | - Yanrong Dong
- Institute of Health Service and Transfusion Medicine, Beijing 100850, P. R. China
| | - Yulong Zhang
- Institute of Health Service and Transfusion Medicine, Beijing 100850, P. R. China
| | - Xiaohui Wang
- Institute of Health Service and Transfusion Medicine, Beijing 100850, P. R. China
| | - Xingyu Jiang
- Guangdong Provincial Key Laboratory of Advanced Biomaterials, Shenzhen Key Laboratory of Smart Healthcare Engineering, Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088 Xueyuan Road, Nanshan District, Shenzhen, Guangdong 518055, P. R. China
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Allegra S, Comità S, Roetto A, De Francia S. Sex and Gender Differences in Iron Chelation. Biomedicines 2024; 12:2885. [PMID: 39767791 PMCID: PMC11673655 DOI: 10.3390/biomedicines12122885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES In the absence of physiological mechanisms to excrete excessive iron, the administration of iron chelation therapy is necessary. Age and hormones have an impact on the absorption, distribution, metabolism, and excretion of the medications used to treat iron excess, resulting in notable sex- and gender-related variances. METHODS Here, we aimed to review the literature on sex and gender in iron overload assessment and treatment. RESULTS The development of iron chelators has shown to be a successful therapy for lowering the body's iron levels and averting the tissue damage and organ failure that follows. Numerous studies have described how individual factors can impact chelation treatment, potentially impact therapeutic response, and/or result in inadequate chelation or elevated toxicity; however, most of these data have not considered male and female patients as different groups, and particularly, the effect of hormonal variations in women have never been considered. CONCLUSIONS An effective iron chelation treatment should take into account sex and gender differences.
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Affiliation(s)
- Sarah Allegra
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga University Hospital, 10043 Orbassano, Italy; (S.C.); (A.R.); (S.D.F.)
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Khan MA. Targeting Iron Responsive Elements (IREs) of APP mRNA into Novel Therapeutics to Control the Translation of Amyloid-β Precursor Protein in Alzheimer's Disease. Pharmaceuticals (Basel) 2024; 17:1669. [PMID: 39770511 PMCID: PMC11677800 DOI: 10.3390/ph17121669] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/30/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
The hallmark of Alzheimer's disease (AD) is the buildup of amyloid-β (Aβ), which is produced when the amyloid precursor protein (APP) misfolds and deposits as neurotoxic plaques in the brain. A functional iron responsive element (IRE) RNA stem loop is encoded by the APP 5'-UTR and may be a target for regulating the production of Alzheimer's amyloid precursor protein. Since modifying Aβ protein expression can give anti-amyloid efficacy and protective brain iron balance, targeted regulation of amyloid protein synthesis through modulation of 5'-UTR sequence function is a novel method for the prospective therapy of Alzheimer's disease. Numerous mRNA interference strategies target the 2D RNA structure, even though messenger RNAs like tRNAs and rRNAs can fold into complex, three-dimensional structures, adding even another level of complexity. The IRE family is among the few known 3D mRNA regulatory elements. This review seeks to describe the structural and functional aspects of IREs in transcripts, including that of the amyloid precursor protein, that are relevant to neurodegenerative diseases, including AD. The mRNAs encoding the proteins involved in iron metabolism are controlled by this family of similar base sequences. Like ferritin IRE RNA in their 5'-UTR, iron controls the production of APP in their 5'-UTR. Iron misregulation by iron regulatory proteins (IRPs) can also be investigated and contrasted using measurements of the expression levels of tau production, Aβ, and APP. The development of AD is aided by iron binding to Aβ, which promotes Aβ aggregation. The development of small chemical therapeutics to control IRE-modulated expression of APP is increasingly thought to target messenger RNAs. Thus, IRE-modulated APP expression in AD has important therapeutic implications by targeting mRNA structures.
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Affiliation(s)
- Mateen A Khan
- Department of Life Science, College of Science and General Studies, Alfaisal University, Riyadh 11533, Saudi Arabia
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Allara E, Bell S, Smith R, Keene SJ, Gill D, Gaziano L, Morselli Gysi D, Wang F, Tragante V, Mason A, Karthikeyan S, Lumbers RT, Bonglack E, Ouwehand W, Roberts DJ, Dowsett J, Ostrowski SR, Larsen MH, Ullum H, Pedersen OB, Brunak S, Banasik K, Erikstrup C, Mitchell J, Fuchsberger C, Pattaro C, Pramstaller PP, Girelli D, Arvas M, Toivonen J, Molnos S, Peters A, Polasek O, Rudan I, Hayward C, McDonnell C, Pirastu N, Wilson JF, van den Hurk K, Quee F, Ferrucci L, Bandinelli S, Tanaka T, Girotto G, Concas MP, Pecori A, Verweij N, van der Harst P, van de Vegte YJ, Kiemeney LA, Sweep FC, Galesloot TE, Sulem P, Gudbjartsson D, Ferkingstad E, Djousse L, Cho K, Inouye M, Burgess S, Benyamin B, Oexle K, Swinkels D, Stefansson K, Magnusson M, Ganna A, Gaziano M, Ivey K, Danesh J, Pereira A, Wood AM, Butterworth AS, Di Angelantonio E. Novel loci and biomedical consequences of iron homoeostasis variation. Commun Biol 2024; 7:1631. [PMID: 39643614 PMCID: PMC11624196 DOI: 10.1038/s42003-024-07115-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 10/21/2024] [Indexed: 12/09/2024] Open
Abstract
Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.
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Affiliation(s)
- Elias Allara
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK.
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
| | - Steven Bell
- Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK
- Cancer Research UK Cambridge Centre, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
| | - Rebecca Smith
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Spencer J Keene
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Liam Gaziano
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Deisy Morselli Gysi
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Statistics, Federal University of Parana, Curitiba, Brazil
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Feiyi Wang
- Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, Helsinki, Finland
| | | | - Amy Mason
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Savita Karthikeyan
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
| | | | - Emmanuela Bonglack
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Willem Ouwehand
- Department of Haematology, University of Cambridge, Cambridge, UK
- NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK
- Department of Haematology, University College London Hospitals NHS Trust, London, UK
| | - David J Roberts
- Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Department of Haematology, Churchill Hospital, Headington, Oxford, UK
| | - Joseph Dowsett
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Margit Hørup Larsen
- Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | | | - Ole Birger Pedersen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Immunology, Zealand University Hospital, Køge, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | | | - Peter P Pramstaller
- Eurac Research, Institute for Biomedicine, Bolzano, Italy
- Department of Neurology, General Central Hospital, Bolzano, Italy
| | - Domenico Girelli
- Department of Medicine, Section of Internal Medicine, EuroBloodNet Referral Center, University Hospital of Verona, Verona, Italy
| | - Mikko Arvas
- Finnish Red Cross Blood Service, Helsinki, Finland
| | | | - Sophie Molnos
- msg life central europe gmbh, München, Germany
- Institute of Epidemiology, Helmholtz Munich, Neuherberg, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, München, Germany
| | - Ozren Polasek
- Faculty of Medicine, University of Split, Split, Croatia
| | - Igor Rudan
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland, Edinburgh, UK
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ciara McDonnell
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland, Edinburgh, UK
- Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, UK
| | - Nicola Pirastu
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland, Edinburgh, UK
- Genomics Research Centre, Human Technopole, Milan, Italy
| | - James F Wilson
- Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland, Edinburgh, UK
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Katja van den Hurk
- Donor Studies, Department of Donor Medicine Research, Sanquin Research, Amsterdam, The Netherlands
- Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Franke Quee
- Donor Studies, Department of Donor Medicine Research, Sanquin Research, Amsterdam, The Netherlands
- Department of Public and Occupational Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Luigi Ferrucci
- Longitudinal studies section, National Institute on Aging, Baltimore, MD, USA
| | | | - Toshiko Tanaka
- Longitudinal studies section, National Institute on Aging, Baltimore, MD, USA
| | - Giorgia Girotto
- Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, Trieste, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Maria Pina Concas
- Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, Trieste, Italy
| | - Alessandro Pecori
- Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, Trieste, Italy
| | - Niek Verweij
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Pim van der Harst
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yordi J van de Vegte
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lambertus A Kiemeney
- IQ Health, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fred C Sweep
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | | - Daniel Gudbjartsson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | | | - Luc Djousse
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Kelly Cho
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael Inouye
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
- Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Australia
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
- Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Stephen Burgess
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
- Medical Research Council Biostatistics Unit, Cambridge, UK
| | - Beben Benyamin
- Australian Centre for Precision Health & Allied Health and Human Performance, University of South Australia, Adelaide, Australia
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Konrad Oexle
- Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany
- Institute of Human Genetics, School of Medicine, Technical University of Munich, München, Germany
| | - Dorine Swinkels
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
- Sanquin Blood Bank, Amsterdam, The Netherlands
| | - Kari Stefansson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Magnus Magnusson
- deCODE genetics/Amgen Inc., Reykjavik, Iceland
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Andrea Ganna
- Genetic Epidemiology Lab, Institute for Molecular Medicine Finland, Helsinki, Finland
| | - Michael Gaziano
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kerry Ivey
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - John Danesh
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
- Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK
| | - Alexandre Pereira
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Angela M Wood
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
- Cambridge Centre of Artificial Intelligence in Medicine, Cambridge, UK
| | - Adam S Butterworth
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
| | - Emanuele Di Angelantonio
- BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK.
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
- BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
- Health Data Science Centre, Human Technopole, Milan, Italy.
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49
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Huo G, Lin Y, Liu L, He Y, Qu Y, Liu Y, Zhu R, Wang B, Gong Q, Han Z, Yin H. Decoding ferroptosis: transforming orthopedic disease management. Front Pharmacol 2024; 15:1509172. [PMID: 39712490 PMCID: PMC11659002 DOI: 10.3389/fphar.2024.1509172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 11/22/2024] [Indexed: 12/24/2024] Open
Abstract
As a mechanism of cell death, ferroptosis has gained popularity since 2012. The process is distinguished by iron toxicity and phospholipid accumulation, in contrast to autophagy, apoptosis, and other cell death mechanisms. It is implicated in the advancement of multiple diseases across the body. Researchers currently know that osteosarcoma, osteoporosis, and other orthopedic disorders are caused by NRF2, GPX4, and other ferroptosis star proteins. The effective relief of osteoarthritis symptoms from deterioration has been confirmed by clinical treatment with multiple ferroptosis inhibitors. At the same time, it should be reminded that the mechanisms involved in ferroptosis that regulate orthopedic diseases are not currently understood. In this manuscript, we present the discovery process of ferroptosis, the mechanisms involved in ferroptosis, and the role of ferroptosis in a variety of orthopedic diseases. We expect that this manuscript can provide a new perspective on clinical diagnosis and treatment of related diseases.
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Affiliation(s)
- Guanlin Huo
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yumeng Lin
- Health Management Center, Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Lusheng Liu
- Department of Acupuncture and Moxibustion, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuqi He
- Department of Blood Transfusion, Lu’an People’s Hospital, The Affiliated Hospital of Anhui Medical University, Lu’an, China
| | - Yi Qu
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yang Liu
- Orthopaedic Center, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Renhe Zhu
- Department of Blood Transfusion, Lu’an People’s Hospital, The Affiliated Hospital of Anhui Medical University, Lu’an, China
| | - Bo Wang
- Department of Orthopaedics, The Eighth Medical Center of PLA General Hospital, Beijing, China
| | - Qing Gong
- Orthopaedic Center, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Zhongyu Han
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Hongbing Yin
- Orthopedic Center, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
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50
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Lo YF, Chang JK. Iron Deficiency in Preschool Children with Chronic Rhinitis. PEDIATRIC ALLERGY, IMMUNOLOGY, AND PULMONOLOGY 2024; 37:98-105. [PMID: 39602172 DOI: 10.1089/ped.2024.0097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Introduction: Iron deficiency (ID) has been intricately linked with various inflammatory diseases. Chronic rhinitis stands as one of most common respiratory inflammation disorders in children. This study aimed to investigate the prevalence of ID among preschool children with chronic rhinitis and to explore the association between ID and chronic rhinitis in this population. Methods: This cross-sectional study included children aged 3 to 7 years diagnosed with chronic rhinitis. ID was defined as transferrin saturation <20%, with absolute ID being defined as ferritin <15 ng/mL. Logistic regression analyses were performed to identify factors associated with ID. Results: A total of 72 children with chronic rhinitis were included, revealing a prevalence of ID of 47.2%. Only 5.9% children with ID exhibited absolute ID. Multivariate analysis revealed that neutrophils (odds ratio [OR] = 1.205, 95% confidence interval [CI] = 1.013-1.433, P = 0.035) and monocytes (OR = 1.803, 95% CI = 1.198-2.713, P = 0.005) were independently and significantly associated with ID. Conclusion: This study revealed a notable prevalence of ID in the preschool children with chronic rhinitis. The significant association between neutrophils and monocytes with ID implied an intricate involvement of innate immunity in the manifestation of ID.
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Affiliation(s)
- Yu-Fang Lo
- Department of Pediatrics, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Jia-Kan Chang
- Department of Pediatrics, Cheng Hsin General Hospital, Taipei, Taiwan
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