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Bangolo A, Amoozgar B, Habibi M, Simms E, Nagesh VK, Wadhwani S, Wadhwani N, Auda A, Elias D, Mansour C, Abbott R, Jebara N, Zhang L, Gill S, Ahmed K, Ip A, Goy A, Cho C. Exploring the gut microbiome’s influence on cancer-associated anemia: Mechanisms, clinical challenges, and innovative therapies. World J Gastrointest Pharmacol Ther 2025; 16:105375. [DOI: 10.4292/wjgpt.v16.i2.105375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 06/03/2025] Open
Abstract
BACKGROUND Anemia is a prevalent and challenging complication in patients with hematologic and solid malignancies, which stems from the direct effects of malignancy, treatment-induced toxicities, and systemic inflammation. It affects patients’ survival, functional status, and quality of life profoundly. Recent literature has highlighted the emerging role of the gut microbiome in the pathogenesis of cancer-associated anemia. The gut microbiota, through its intricate interplay with iron metabolism, inflammatory pathways, and immune modulation, may either exacerbate or ameliorate anemia depending on its composition, and functional integrity. Dysbiosis, characterized by disruption in the gut microbial ecosystem, is very common in cancer patients. This microbial imbalance is implicated in anemia causation through diminished iron absorption, persistent low-grade inflammation, and suppression of erythropoiesis.
AIM To consolidate current evidence regarding the interplay between gut microbiome and anemia in the setting of malignancies. It aims to provide a detailed exploration of the mechanistic links between dysbiosis and anemia, identifies unique challenges associated with various cancer types, and evaluates the efficacy of microbiome-focused therapies. Through this integrative approach, the review seeks to establish a foundation for innovative clinical strategies aimed at mitigating anemia and improving patient outcomes in oncology.
METHODS A literature search was performed using multiple databases, including Google Scholar, PubMed, Scopus, and Web of Science, using a combination of keywords and Boolean operators to refine results. Keywords included “cancer-associated anemia”, “gut microbiome”, “intestinal microbiota”, “iron metabolism”, “gut dysbiosis”, “short-chain fatty acids”, “hematopoiesis”, “probiotics”, “prebiotics”, and “fecal microbiota transplantation”. Articles published in English between 2000 and December 2024 were included, with a focus on contemporary and relevant findings.
RESULTS Therapeutic strategies aimed at restoration of gut microbial homeostasis, such as probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation (FMT), can inhibit anemia-causing pathways by enhancing microbial diversity, suppressing detrimental flora, reducing systemic inflammation and optimizing nutrient absorption.
CONCLUSION Gut dysbiosis causes anemia and impairs response to chemotherapy in cancer patients. Microbiome-centered interventions, such as probiotics, prebiotics, dietary modifications, and FMT, have shown efficacy in restoring microbial balance, reducing inflammation, and enhancing nutrient bioavailability. Emerging approaches, including engineered probiotics and bacteriophage therapies, are promising precision-based, customizable solutions for various microbiome compositions and imbalances. Future research should focus on integrating microbiome-targeted strategies with established anemia therapies.
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Affiliation(s)
- Ayrton Bangolo
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Behzad Amoozgar
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Maryam Habibi
- Department of Research, Tulane National Primate Research Center, Covington, LA 70433, United States
| | - Elizabeth Simms
- Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, United States
| | - Vignesh K Nagesh
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Shruti Wadhwani
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Nikita Wadhwani
- Department of Internal Medicine, Hackensack Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Auda Auda
- Department of Family Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Daniel Elias
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Charlene Mansour
- Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Robert Abbott
- Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nisrene Jebara
- Columbia University School of Nursing, New York, NY 10032, United States
| | - Lili Zhang
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Sarvarinder Gill
- Department of Hematology and Oncology, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Kareem Ahmed
- Department of Medicine, University of Washington, Seattle, WA 98195, United States
| | - Andrew Ip
- Division of Lymphoma, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Andre Goy
- Division of Lymphoma, John Theurer Cancer Center, Hackensack, NJ 07601, United States
| | - Christina Cho
- Division of Stem Cell Transplant and Cellular Therapy, John Theurer Cancer Center, Hackensack, NJ 07601, United States
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Gangat N, Tefferi A. Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes. Am J Hematol 2025; 100 Suppl 4:51-65. [PMID: 40056069 DOI: 10.1002/ajh.27659] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/20/2025] [Accepted: 02/27/2025] [Indexed: 05/13/2025]
Abstract
Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin-induced iron-restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF-β)-bone morphogenic protein/sons of mothers against decapentaplegic (BMP-SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.
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Affiliation(s)
- Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayalew Tefferi
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
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Lobbes H, Pereira B, Richard M, Roux-Perceval M, Durieu I, Reynaud Q. Improvement of iron status with elexacaftor tezacaftor ivacaftor therapy is associated with the correction of systemic inflammation and improvement of lung function: a one-year prospective study. Sci Rep 2025; 15:17394. [PMID: 40389628 PMCID: PMC12089272 DOI: 10.1038/s41598-025-02296-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 05/13/2025] [Indexed: 05/21/2025] Open
Abstract
Iron deficiency (ID) is frequent in adult patients with cystic fibrosis (pwCF). The effect of elexacaftor-tezacaftor-ivacaftor (ETI) on iron metabolism has rarely been reported. We aimed to study the trends and variables associated with iron store modulation under ETI. We conducted a prospective adult cohort in two referral centres for pwCF. Iron supplementation during the follow-up was an exclusion criterion. Clinical, biological data and pulmonary function tests were collected prospectively at ETI initiation (V0) and after 1 year of ETI (V12). The presence of Pseudomonas aeruginosa in forced sputum was assessed at V0 and V12. 220 (87 women) pwCF among the 278 screened were included. At V0, ID prevalence was 58% and was significantly associated with female sex and lower forced expiratory volume (FEV1). At V12, ID prevalence decreased significantly from 58 to 31% (p = 0.001). A significant decrease of C reactive protein and total globulins was found at V12. 60% of patients with ID at V0 achieved normalization of iron status at V12 with a significant association with the increase of FEV1 (moderate size effect: 0.68). A lower decrease of C reactive protein was significantly associated with the onset of ID in a small sample of patients (p < 0.001). The disappearance of Pseudomonas aeruginosa in sputum at V12 was not correlated to the evolution of iron status under ETI. ETI was associated with a decrease of ID prevalence, and improvement of pulmonary function and a correction of systemic inflammation.
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Affiliation(s)
- Hervé Lobbes
- Service de Médecine Interne, Hôpital Estaing, Centre Hospitalier Universitaire de Clermont-Ferrand, 1 Place Lucie et Raymond Aubrac, Clermont-Ferrand, 63100, France.
- Institut Pascal, UMR 6602, Université Clermont Auvergne, Clermont-Ferrand, France.
| | - Bruno Pereira
- Unité de Biostatistiques, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France
| | - Maël Richard
- Centre de référence mucoviscidose, Service de médecine Interne, Centre Hospitalier Universitaire Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Marie Roux-Perceval
- Centre de référence mucoviscidose, Service de médecine Interne, Centre Hospitalier Universitaire Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Isabelle Durieu
- Centre de référence mucoviscidose, Service de médecine Interne, Centre Hospitalier Universitaire Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
- Research on healthcare performance (REHSAPE) Inserm U1290, Université Lyon 1, Lyon, France
| | - Quitterie Reynaud
- Centre de référence mucoviscidose, Service de médecine Interne, Centre Hospitalier Universitaire Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
- Research on healthcare performance (REHSAPE) Inserm U1290, Université Lyon 1, Lyon, France
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Matsuoka T, Tomita H, Tagami T, Maruyama N, Yasuo M, Nagura C, Tsunemi A, Nakamura Y, Maruyama T, Abe M, Kobayashi H. Limited Utility of Serum Hepcidin as a Marker for Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients: An Analysis From the INFINITY Cohort. Ther Apher Dial 2025. [PMID: 40371877 DOI: 10.1111/1744-9987.70040] [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: 02/22/2025] [Revised: 04/14/2025] [Accepted: 04/28/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND Although erythropoiesis-stimulating agents (ESAs) have improved anemia management, some patients on maintenance hemodialysis (HD) exhibit hyporesponsiveness. Hepcidin, a key regulator of iron homeostasis, may play a role in this process. However, its potential as a marker for ESA hyporesponsiveness remains unclear due to conflicting findings of previous studies. This study aimed to evaluate serum hepcidin-25 as a marker for ESA hyporesponsiveness and identify factors influencing hepcidin levels in HD patients. METHODS This prospective observational study included 478 HD patients receiving ESA from the INFINITY cohort. Blood samples were collected before and after ESA administration to measure serum hepcidin-25. ESA hyporesponsiveness was defined by an erythropoietin resistance index (ERI) of 15 or higher. Logistic regression and linear regression analyses were used to identify factors associated with ESA hyporesponsiveness and hepcidin levels. RESULTS Among patients receiving ESAs, 15% were classified as hyporesponsive. In the darbepoetin alpha group, hyporesponsive patients had lower hepcidin-25 levels; however, this association was not retained in multivariable analysis. No difference in hepcidin was observed in the recombinant human erythropoietin (EPO) group. Higher C-reactive protein (CRP), ferritin, transferrin saturation (TSAT), albumin, and glycoalbumin were linked to increased hepcidin, while being male and higher ESA dosage were associated with lower hepcidin levels. CONCLUSIONS Hepcidin-25 levels were lower in ESA hyporesponsive patients; however, the association was not significant in multivariable analysis. Thus, routine measurement of hepcidin may not be necessary for diagnosing ESA hyporesponsiveness. The novel association between hepcidin and glycoalbumin suggests an interaction between iron regulation and glucose metabolism, warranting further study.
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Affiliation(s)
- Tomomi Matsuoka
- Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hyoe Tomita
- Yujin Clinic, Tokyo, Japan
- Yujin Oizumigakuen Clinic, Tokyo, Japan
| | | | | | | | - Chinami Nagura
- Shiki Ekimae Clinic, Saitama, Japan
- Asakadai Dialysis Clinic, Saitama, Japan
| | - Akiko Tsunemi
- Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Yoshihiro Nakamura
- Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Maruyama
- Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Masanori Abe
- Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hiroki Kobayashi
- Division of Nephrology, Hypertension, and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
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Wu J, Liu J, Chen J, Yang L, Li F, Qin T, Xu Z, Liu J, Zhou J, Shi L, Li B, Xiao Z. A correlation of ineffective erythropoiesis and dysregulated signaling pathways in myelodysplastic syndromes/neoplasms. Exp Hematol Oncol 2025; 14:71. [PMID: 40369677 PMCID: PMC12079896 DOI: 10.1186/s40164-025-00664-1] [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: 11/27/2024] [Accepted: 05/01/2025] [Indexed: 05/16/2025] Open
Abstract
Over 90% of patients with myelodysplastic syndromes/neoplasms (MDS) exhibit anemia at diagnosis, primarily due to ineffective erythropoiesis. This is characterized by abnormal proliferation and differentiation of erythroid cells influenced by signaling pathways including heme synthesis, ferroptosis, senescence and apoptosis. Despite widespread anemia, the specific mechanisms and pathway alterations at different disease stages are not well understood. This study employed the NUP98-HOXD13 (NHD13) transgenic mouse model, which mimicked the erythroid changes observed in MDS patients, to explore these dynamic pathway changes during disease progression. Based on the severity of anemia and changes in mean corpuscular volume (MCV), four time points were selected: 6 weeks (non-anemic), 12 weeks (mild anemia), 16 weeks (obvious anemia) and 20 weeks (severe macrocytic anemia). The findings indicated that a reduction in erythroid-committed progenitors and impaired erythroid maturation were linked to ineffective erythropoiesis. As the disease progressed, signaling pathways dynamically changed. Heme metabolism and ferroptosis pathways were significantly upregulated in the pre-disease and early disease stages, while senescence and cell cycle pathways were activated in the early stage. The prominent roles of apoptosis, pyroptosis and inflammasome signaling pathways were observed in the late stage. Notably, changes in Gpx4 and Ncoa4 expression, along with transmission electron microscopy analysis, suggested that ferroptosis played a critical role in the early stage of the disease. To our knowledge, this is the first report of the signaling pathway dynamics associated with ineffective erythropoiesis during the pathogenesis and progression of MDS, highlighting potential targets for therapeutic intervention at various stages of the disease.
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Affiliation(s)
- Junying Wu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jinqin Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jia Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lin Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Fuhui Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Tiejun Qin
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zefeng Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Jing Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jiaxi Zhou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lihong Shi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Bing Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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Quintana-Castanedo L, Maseda R, Pérez-Conde I, Butta N, Monzón-Manzano E, Acuña-Butta P, Crespo MG, Buño-Soto A, Jiménez E, Valencia J, Arriba MC, Zuluaga P, de Lucas R, Del Río M, Vicente Á, Escámez MJ, Sacedón R. Interplay between iron metabolism, inflammation, and EPO-ERFE-hepcidin axis in RDEB-associated chronic anemia. Blood Adv 2025; 9:2321-2335. [PMID: 40036737 DOI: 10.1182/bloodadvances.2024015271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/11/2025] [Accepted: 02/18/2025] [Indexed: 03/06/2025] Open
Abstract
ABSTRACT Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterized by severe cutaneous and mucosal fragility, and frequently complicated by multifactorial chronic anemia that responds poorly to conventional therapies. This cross-sectional study investigates the factors contributing to anemia in RDEB by analyzing a representative cohort, that was stratified by disease severity, anemia, and iron status, to examine their hematological parameters, cytokine profile, and the erythropoietin-erythroferrone-hepcidin (EPO-ERFE-hepcidin) axis. Anemia was present in 50% of the cohort. Hemoglobin levels showed a strong negative correlation with the percentage of body surface area affected and C-reactive protein levels (CRP), identifying these as anemia risk factors in RDEB. Moderate-severe inflammation (CRP ≥ 15 mg/L) was observed in all patients with anemia, but no specific cytokine profile was linked with anemia risk because of variability in interleukin-6 (IL-6), IL-1β, IL-10, tumor necrosis factor, and interferon-γ levels. The regulation of the EPO-ERFE-hepcidin axis showed discrepancies with the patterns expected based on patients' anemia severity and iron status. According to the reticulocyte production index, an inadequate bone marrow response was observed in 90% of patients with anemia, irrespective of EPO levels. Patients with functional or true iron deficiency had higher ERFE levels, although ERFE showed no consistent correlation with EPO and was elevated in both patients with anemia and those without anemia. Elevated hepcidin was primarily linked to the highest ferritin levels, mostly in patients with a history of iron infusions and/or transfusions. These findings highlight the need for personalized, targeted approaches that address the complex interplay between inflammation and iron dysregulation, to improve anemia management in RDEB and other chronic inflammatory conditions.
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Affiliation(s)
- Lucía Quintana-Castanedo
- Department of Dermatology, Hospital La Paz, Madrid, Spain
- Department of Dermatology, Marqués de Valdecilla University Hospital, Santander, Spain
| | - Rocío Maseda
- Department of Dermatology, Hospital La Paz, Madrid, Spain
| | | | - Nora Butta
- Department of Hematology and Hemotherapy, Hospital La Paz, Madrid, Spain
- Coagulopathies and Alterations in Haemostasis Group, IdiPAZ Health Research Institute, Hospital La Paz, Madrid, Spain
| | - Elena Monzón-Manzano
- Department of Hematology and Hemotherapy, Hospital La Paz, Madrid, Spain
- Coagulopathies and Alterations in Haemostasis Group, IdiPAZ Health Research Institute, Hospital La Paz, Madrid, Spain
| | - Paula Acuña-Butta
- Department of Hematology and Hemotherapy, Hospital La Paz, Madrid, Spain
- Coagulopathies and Alterations in Haemostasis Group, IdiPAZ Health Research Institute, Hospital La Paz, Madrid, Spain
| | - María G Crespo
- Department of Laboratory Medicine, Hospital La Paz, Madrid, Spain
| | - Antonio Buño-Soto
- Department of Laboratory Medicine, Hospital La Paz, Madrid, Spain
- Neonatology Group, IdiPAZ Health Research Institute, Hospital La Paz, Madrid, Spain
| | - Eva Jiménez
- Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
- Immunology Group, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Jaris Valencia
- Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
- Immunology Group, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - María C Arriba
- Departamento de Bioingeniería, Universidad Carlos III de Madrid, Madrid, Spain
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras-Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Pilar Zuluaga
- Department of Statistics and Operations Research, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Raúl de Lucas
- Department of Dermatology, Hospital La Paz, Madrid, Spain
| | - Marcela Del Río
- Departamento de Bioingeniería, Universidad Carlos III de Madrid, Madrid, Spain
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras-Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ángeles Vicente
- Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
- Stem Cells, Immunity and Cancer Group, Health Research Institute Hospital 12 de Octubre (I+12), Madrid, Spain
| | - María J Escámez
- Departamento de Bioingeniería, Universidad Carlos III de Madrid, Madrid, Spain
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras-Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Rosa Sacedón
- Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
- Immunology Group, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
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7
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Wang X, Lipiński P, Ogłuszka M, Mazgaj R, Woliński J, Szkopek D, Zaworski K, Kopeć Z, Żelazowska B, Tarantino G, Brilli E, Starzyński RR. Oral supplementation with Sucrosomial® Iron improves the iron status of preterm piglets delivered by cesarean section. Food Funct 2025; 16:3525-3541. [PMID: 40227702 DOI: 10.1039/d4fo04806g] [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: 04/15/2025]
Abstract
Premature infants are more likely to develop iron deficiency caused by an inadequate iron storage due to shortened pregnancy. Sucrosomial® Iron (SI) is an oral iron formulation of ferric pyrophosphate with high bioavailability and tolerability. This research compared the iron status of preterm and full-term piglets and evaluated the effects of SI on iron homeostasis in the early postnatal period. Eighteen preterm piglets (born via cesarean section on gestation day 109) and twelve full-term piglets (natural birth) were divided into five groups (n = 6 piglets per group): full-term/preterm piglets without iron supplementation, full-term/preterm piglets supplemented with SI (2 mg Fe per piglet per day, days 4-10), and preterm piglets supplemented with ferrous sulfate (2 mg Fe per piglet per day, days 4-10). Samples were collected on day 11. Preterm piglets showed poor growth and low total body iron content, and they developed iron deficiency anemia, as indicated by decreased red blood cell indices and plasma iron parameters. The iron deficiency was partially improved by SI supplementation. Interestingly, higher hepatic and splenic non-heme iron content, accompanied by increased tissue and plasma ferritin, were found in preterm piglets compared to full-term piglets. SI also contributed to tissue iron accumulation in preterm piglets. Functional iron deficiency and iron accumulation in tissues make the regulation of iron metabolism in preterm piglets different from that in full-term ones. SI can alleviate the negative effects of iron imbalances caused by premature birth by regulating the hepcidin-ferroportin axis. In addition, SI did not induce inflammatory or oxidative responses, and its effects are comparable to those of the classic iron supplement, ferrous sulfate. These results indicate that SI is a promising iron supplement for improving the iron status of premature infants.
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Affiliation(s)
- Xiuying Wang
- Laboratory of Iron Molecular Biology, Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland.
| | - Paweł Lipiński
- Laboratory of Iron Molecular Biology, Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland.
| | - Magdalena Ogłuszka
- Department of Genomics and Biodiversity, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland
| | - Rafał Mazgaj
- Laboratory of Iron Molecular Biology, Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland.
| | - Jarosław Woliński
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05110 Jabłonna, Poland
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05110 Jabłonna, Poland
| | - Dominika Szkopek
- Laboratory of Large Animal Models, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05110 Jabłonna, Poland
| | - Kamil Zaworski
- Department of Animal Physiology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, 05110 Jabłonna, Poland
| | - Zuzanna Kopeć
- Laboratory of Iron Molecular Biology, Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland.
| | - Beata Żelazowska
- Laboratory of Iron Molecular Biology, Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland.
| | | | - Elisa Brilli
- Scientific Department, Pharmanutra S.p.A., 56122 Pisa, Italy
| | - Rafał Radosław Starzyński
- Laboratory of Iron Molecular Biology, Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05552 Jastrzębiec, Poland.
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8
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Choudhary S, Picut C, Vargas SR, Otis D, Coskran TM, Karanian D, DaSilva JK, Houle C, Whiteley LO. Mesangial cell hypercellularity and iron accumulation in the kidney associated with administration of a sickle hemoglobin modulator in CD-1 mice. Vet Pathol 2025; 62:397-407. [PMID: 39711519 DOI: 10.1177/03009858241306400] [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: 12/24/2024]
Abstract
The kidney plays an important role in iron homeostasis and mesangial cells (MCs) are phagocytic cells important for glomerular homeostasis. Sickle hemoglobin (HbS) modulators are promising clinical candidates for treatment of sickle cell disease. Although they prevent disease pathophysiology of HbS polymerization and red blood cell (RBC) sickling by increasing hemoglobin oxygen affinity, higher oxygen affinity can also cause transient tissue hypoxia with compensatory increases in erythropoiesis and subsequent increases in RBC turnover. CD-1 mice treated with an HbS modulator for 2 weeks developed higher RBC mass, increased erythropoiesis, and, by 1 month, deposition of intracellular pigments in renal tubular and parietal epithelium. In addition, in mice treated for 26 weeks, pigment was observed in MCs, which was accompanied by glomerular cell aggregates (MC hypercellularity) and tubulo-interstitial inflammation. The pigment was confirmed by Perl's iron staining and transmission electron microscopy (TEM) to be iron-containing proteins. Glomerular cell aggregates were confirmed to be MCs by TEM, and Ki-67 immunolabeling suggested that MC hypercellularity was due to proliferation. Collectively, these findings, along with iron-containing proteins in livers and spleens, suggested that iron overload secondary to increased RBC turnover led to increased renal iron reabsorption. While both MC hypercellularity and tubulo-interstitial inflammation were thought to be responses to long-term accumulation of iron, the former was considered a homeostatic response to eliminate iron, and maintain glomerular structure and function, while the latter was more consistent with an iron-catalyzed oxidative stress response. To our knowledge, this is the first report of MC hypercellularity in a preclinical toxicity study.
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9
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Crisafulli L, Correnti M, Gammella E, De Camilli E, Brindisi M, Palagano E, Milanesi C, Todisco G, Della Porta MG, Sobacchi C, Cairo G, Ficara F, Recalcati S. Iron trapping in macrophages reshapes the homeostasis of the haematopoietic system. Br J Haematol 2025; 206:1485-1496. [PMID: 40012014 PMCID: PMC12078876 DOI: 10.1111/bjh.20031] [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: 05/28/2024] [Accepted: 02/14/2025] [Indexed: 02/28/2025]
Abstract
Iron is required for key physiological processes, like oxygen transport, energy production and cell proliferation. Body iron homeostasis is regulated by the erythroferrone-hepcidin-ferroportin (FPN) axis, which mainly acts on absorptive duodenal cells and macrophages involved in iron recycling from red blood cell breakdown. In addition to systemic iron regulation, macrophages are also involved in local iron release to neighbouring cells. Similarly, bone marrow (BM)-resident macrophages could represent promptly available local sources of iron for developing haematopoietic cells. To study the impact of macrophage-released iron on BM haematopoietic stem and progenitor cells, we employed mice with targeted deletion of Fpn in the myeloid lineage (Fpn conditional knockout or Fpn-cKO). Fpn-cKO mice develop age-related anaemia and microcytaemia, reduction of BM erythroblasts and preferential megakaryopoiesis at the expenses of erythropoiesis, suggesting that red cells are mostly affected by the lack of myeloid-derived iron delivery. Transferrin receptor 1 surface expression is higher in Fpn-cKO mice than littermate controls in all the BM subpopulation analysed, starting from haematopoietic stem cells, indicating a broad BM sensitivity to lower iron availability. Last, Fpn-cKO mice activate systemic compensatory mechanisms, such as extramedullary haematopoiesis and erythroferrone upregulation, albeit not sufficient to overcome anaemia.
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Affiliation(s)
- Laura Crisafulli
- Milan UnitCNR‐IRGBMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
| | | | - Elena Gammella
- Department of Biomedical Sciences for HealthUniversity of MilanMilanItaly
| | - Elisa De Camilli
- Division of Pathology, IEOEuropean Institute of Oncology IRCCSMilanItaly
| | - Matteo Brindisi
- Milan UnitCNR‐IRGBMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
| | - Eleonora Palagano
- IRCCS Humanitas Research HospitalMilanItaly
- Institute of Biosciences and BioresourcesCNRFlorenceItaly
| | | | - Gabriele Todisco
- IRCCS Humanitas Research HospitalMilanItaly
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly
| | - Matteo G. Della Porta
- IRCCS Humanitas Research HospitalMilanItaly
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly
| | - Cristina Sobacchi
- Milan UnitCNR‐IRGBMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
| | - Gaetano Cairo
- Department of Biomedical Sciences for HealthUniversity of MilanMilanItaly
| | - Francesca Ficara
- Milan UnitCNR‐IRGBMilanItaly
- IRCCS Humanitas Research HospitalMilanItaly
| | - Stefania Recalcati
- Department of Biomedical Sciences for HealthUniversity of MilanMilanItaly
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10
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Saeed BI, Uthirapathy S, Kubaev A, Ganesan S, Shankhyan A, Gupta S, Joshi KK, Kariem M, Jasim AS, Ahmed JK. Ferroptosis as a key player in the pathogenesis and intervention therapy in liver injury: focusing on drug-induced hepatotoxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04115-w. [PMID: 40244448 DOI: 10.1007/s00210-025-04115-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025]
Abstract
Globally, drug-induced hepatotoxicity or drug-induced liver injury (DILI) is a serious clinical concern. Knowing the processes and patterns of cell death is essential for finding new therapeutic targets since there are not many alternatives to therapy for severe liver lesions. Excessive lipid peroxidation is a hallmark of ferroptosis, an iron-reliant non-apoptotic cell death linked to various liver pathologies. When iron is pathogenic, concomitant inflammation may exacerbate iron-mediated liver injury, and the hepatocyte necrosis that results is a key element in the fibrogenic response. The idea that dysregulated metabolic pathways and compromised iron homeostasis contribute to the development of liver injury by ferroptosis is being supported by new data. Various ferroptosis-linked genes and pathways have been linked to liver injury, although the molecular processes behind ferroptosis's pathogenicity are not well known. Here, we delve into the features of ferroptosis, the processes governing ferroptosis, and our current knowledge of iron metabolism. We also provide an overview of ferroptosis's involvement in the pathophysiology of liver injury, particularly DILI. Lastly, the therapeutic possibilities of ferroptosis targeting for liver injury management have been provided. Natural products, nanoparticles (NPs), mesenchymal stem cell (MSC), and their exosomes have attracted increasing attention among such therapeutics.
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Affiliation(s)
- Bahaa Ibrahim Saeed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, University of Al-Maarif, Anbar, Iraq
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, 18 Amir Temur Street, 140100, Samarkand, Uzbekistan.
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Aman Shankhyan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Sofia Gupta
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, India
- Graphic Era Deemed to be University, Dehradun, Uttarakhand, India
| | - Muthena Kariem
- Department of Medical Analysis, Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
| | - Ahmed Salman Jasim
- Radiology Techniques Department College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
| | - Jawad Kadhim Ahmed
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
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11
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Harrison CN, Barbui T, Bose P, Kiladjian JJ, Mascarenhas J, McMullin MF, Mesa R, Vannucchi AM. Polycythaemia vera. Nat Rev Dis Primers 2025; 11:26. [PMID: 40246933 DOI: 10.1038/s41572-025-00608-3] [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] [Accepted: 03/14/2025] [Indexed: 04/19/2025]
Abstract
Polycythaemia vera (PV) is a haematological malignancy in the myeloproliferative neoplasm family. PV is typically characterized by erythrocytosis and often leukocytosis and thrombocytosis1. Clinical features include reduced life expectancy due to hazards of thrombosis (often in atypical sites), haemorrhage and transformation to myelofibrosis and less frequently to a form of acute myeloid leukaemia called blast phase. Almost two decades ago, the JAK2V617F mutation in exon 14 of JAK2 was described, and is known to be present in more than 95% of patients with PV. Testing for the JAK2V617F mutation is used in the diagnosis of PV, and the quantity of the mutation (that is, the variant allele frequency) is linked to prognosis and the risk of complications. As such, reduction of JAK2V617F variant allele frequency is currently being evaluated as a treatment target. Recommendations for PV treatment include control of vascular risk factors, therapeutic phlebotomy and low-dose aspirin in all patients. Currently, patients at higher risk of thrombosis (aged over 60 years and/or with a history of thrombosis) are offered cytoreductive agents. Hydroxyurea or interferons remain the preferred first-line cytoreductive agents, with the JAK1 and JAK2 inhibitor, ruxolitinib, currently approved for the treatment of patients who are resistant to, or intolerant of, hydroxyurea. Future recommendations might be to treat the majority of patients with these agents as long-term benefits of treatment begin to emerge.
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Affiliation(s)
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Prithviraj Bose
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Jacques Kiladjian
- AP-HP, Hopital Saint-Louis, Centre d'Investigations Cliniques CIC 1427, Université Paris Cité, Inserm, Paris, France
| | - John Mascarenhas
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Ruben Mesa
- Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, USA
| | - Alessandro M Vannucchi
- Center Research and Innovation Myeloproliferative Neoplasms, University of Florence and AOU Careggi, Florence, Italy
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12
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Zhang S, Hu X, Sun M, Chen X, Le S, Wang X, Wang J, Hu Z. Potential role of hypobaric hypoxia environment in treating pan-cancer. Sci Rep 2025; 15:12942. [PMID: 40234469 PMCID: PMC12000279 DOI: 10.1038/s41598-024-84561-3] [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: 07/30/2024] [Accepted: 12/24/2024] [Indexed: 04/17/2025] Open
Abstract
Cancer incidence and mortality are lower among high-altitude residents, suggesting that hypobaric hypoxia (HH) might protect against cancer. Our study aimed to develop a pan-cancer prognosis risk model using ADME genes, which are influenced by low oxygen, to explore HH's impact on overall survival (OS) across various cancers. We constructed and validated the model with gene expression and survival data from 8628 samples, using three gene expression databases. AltitudeOmics confirmed HH's significant effects. We employed single-gene prognostic analysis, weighted gene co-expression network analysis, and stepwise Cox regression to identify biomarkers and refine the model. Drugs interacting with the model were explored using LINCS L1000, AutoDockTools, and STITCH. Eight ADME genes significantly altered by HH were identified, revealing their prognostic value across cancers. The model showed lower risk scores linked to better prognosis in 25 cancers, with reduced overall gene expression and decreased tumor mortality risk. Higher T cell infiltration was observed in the low-risk group. Additionally, three potential drugs to modulate our model were identified. This study presents a novel pan-cancer survival prognosis model based on ADME genes influenced by HH, offering new insights into cancer prevention and treatment.
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Affiliation(s)
- Shixuan Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | - Xiaoxi Hu
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | - Mengzhen Sun
- Zhangjiang Fudan International Innovation Centre, Human Phenome Institute, Fudan University, Shanghai, China
| | - Xinrui Chen
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | - Shiguan Le
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | - Xilu Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China
| | - Jiucun Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China.
| | - Zixin Hu
- State Key Laboratory of Genetic Engineering, School of Life Sciences & Human Phenome Institute, Fudan University, Shanghai, 200438, China.
- Artificial Intelligence Innovation and Incubation Institute, Fudan University, Shanghai, China.
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13
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Dubach IL, Buzzi RM, Schaer DJ, Vallelian F. Patterns of hemolysis, erythropoiesis, and iron distribution define unique disease trajectories in three mouse models of genetic anemia. Exp Hematol 2025; 147:104787. [PMID: 40245977 DOI: 10.1016/j.exphem.2025.104787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/08/2025] [Accepted: 04/09/2025] [Indexed: 04/19/2025]
Abstract
Hemolytic anemias involve premature red blood cell (RBC) destruction and present complex phenotypes, including disturbances in iron metabolism, extramedullary erythropoiesis, and systemic organ involvement. To guide the selection of appropriate murine models for studying pathophysiology and pharmacologic treatments of human hemolytic disorders, we systematically characterized three genetic mouse models commonly used to investigate such conditions: sickle cell disease (SCD), β-thalassemia (THAL), and hereditary spherocytosis (SPH). We sought to clarify how these models differ in the severity and nature of hemolysis, the balance between erythropoietic responses and iron regulation, and the long-term patterns of iron distribution. Our findings reveal that SPH mice exhibit severe intravascular hemolysis and suppressed hepcidin levels, leading to unopposed intestinal iron absorption and extensive tissue iron loading, especially in the liver. In contrast, SCD and THAL mice display predominantly extravascular hemolysis, moderate anemia, relatively stable hepcidin levels, and balanced erythropoiesis with partially regulated iron overload. Single-cell ribonucleic acid (RNA) sequencing of spleens highlighted distinct erythropoietic progenitor distributions, whereas iron-isotope tracing experiments confirmed divergent RBC turnover kinetics and tissue distribution. This study defines distinct disease trajectories for common hemolytic disease models by providing a unique comparative framework. Our work will support more informed model selection and refined experimental design to investigate hemolytic anemia pathobiology and therapeutics.
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Affiliation(s)
- Irina L Dubach
- Division of Internal Medicine, University of Zurich, Zurich, Switzerland
| | - Raphael M Buzzi
- Division of Internal Medicine, University of Zurich, Zurich, Switzerland
| | - Dominik J Schaer
- Division of Internal Medicine, University of Zurich, Zurich, Switzerland
| | - Florence Vallelian
- Division of Internal Medicine, University of Zurich, Zurich, Switzerland.
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14
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Kuorelahti T, Ihalainen JK, Linnamo V, Badenhorst C, Kettunen O, Mikkonen RS. Influence of "live high-train low" on hemoglobin mass and post-exercise hepcidin response in female endurance athletes. Eur J Appl Physiol 2025:10.1007/s00421-025-05762-w. [PMID: 40210726 DOI: 10.1007/s00421-025-05762-w] [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] [Received: 10/30/2024] [Accepted: 03/18/2025] [Indexed: 04/12/2025]
Abstract
PURPOSE The aim of this study was to investigate the effects of a 21-day 'live high-train low' (LHTL) intervention on hemoglobin mass (Hbmass) and post-exercise hepcidin response in female endurance athletes. METHODS 15 national to international level female endurance athletes completed either the LHTL intervention in normobaric hypoxia (2500 m, ~ 18 h·day-1, INT, n = 7) or lived and trained in normoxia for the same duration (CON, n = 8). Tests were conducted before (PRE) and within two days after (POST) the intervention including Hbmass measurements via a carbon monoxide rebreathing method and a roller skiing skate test. Venous blood samples were collected at rest, 0, and 3 h after the aerobic exercise to test for changes in serum hepcidin, ferritin, and interleukin-6 (IL-6). RESULTS Normobaric hypoxia increased Hbmass (3.3 ± 1.8%, p < 0.001) in INT, while no changes were observed in CON. There were no changes in performance parameters, resting levels of hepcidin, or IL-6 from PRE to POST, but ferritin decreased in both groups (p = 0.040). Hepcidin increased 0 h post-exercise in PRE for INT (p = 0.029) and both 0 and 3 h post-exercise for CON (p = 0.001, p = 0.019). In POST elevated post-exercise hepcidin was only observed in CON (0 h, p = 0.003; 3 h, p = 0.008). CONCLUSIONS 21-day LHTL increased Hbmass and suppressed post-exercise hepcidin response after intensive aerobic exercise. This suggests that prolonged hypoxia may induce an acute physiological response that supports iron absorption within a few days following hypoxic exposure, which may assist in achieving the aerobic adaptations sought from prolonged hypoxic training camps.
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Affiliation(s)
- Titta Kuorelahti
- Sports Technology Unit Vuokatti, Faculty of Sport and Health Sciences, University of Jyväskylä, Vuokatti, Finland.
| | - Johanna K Ihalainen
- Sports Technology Unit Vuokatti, Faculty of Sport and Health Sciences, University of Jyväskylä, Vuokatti, Finland
| | - Vesa Linnamo
- Sports Technology Unit Vuokatti, Faculty of Sport and Health Sciences, University of Jyväskylä, Vuokatti, Finland
| | - Claire Badenhorst
- School of Sport, Exercise and Nutrition, Massey University, Auckland, New Zealand
| | - Oona Kettunen
- Sports Technology Unit Vuokatti, Faculty of Sport and Health Sciences, University of Jyväskylä, Vuokatti, Finland
| | - Ritva S Mikkonen
- Sports Technology Unit Vuokatti, Faculty of Sport and Health Sciences, University of Jyväskylä, Vuokatti, Finland
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15
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Dong Y, Zheng M, Ding W, Guan H, Xiao J, Li F. Nrf2 activators for the treatment of rare iron overload diseases: From bench to bedside. Redox Biol 2025; 81:103551. [PMID: 39965404 PMCID: PMC11876910 DOI: 10.1016/j.redox.2025.103551] [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: 01/08/2025] [Revised: 02/02/2025] [Accepted: 02/13/2025] [Indexed: 02/20/2025] Open
Abstract
Iron overload and related oxidative damage are seen in many rare diseases, due to mutation of iron homeostasis-related genes. As a core regulator on cellular antioxidant reaction, Nrf2 can also decrease systemic and cellular iron levels by regulating iron-related genes and pathways, making Nrf2 activators very good candidates for the treatment of iron overload disorders. Successful examples include the clinical use of omaveloxolone for Friedreich's Ataxia and dimethyl fumarate for relapsing-remitting multiple sclerosis. Despite these uses, the therapeutic potentials of Nrf2 activators for iron overload disorders may be overlooked in clinical practice. Therefore, this study talks about the potential use, possible mechanisms, and precautions of Nrf2 activators in treating rare iron overload diseases. In addition, a combination therapy with Nrf2 activators and iron chelators is proposed for clinical reference, aiming to facilitate the clinical use of Nrf2 activators for more iron overload disorders.
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Affiliation(s)
- Yimin Dong
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Zheng
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weizhong Ding
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hanfeng Guan
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jun Xiao
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Feng Li
- Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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16
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Yang W, Peng M, Wang Y, Zhang X, Li W, Zhai X, Wu Z, Hu P, Chen L. Deletion of hepcidin disrupts iron homeostasis and hematopoiesis in zebrafish embryogenesis. Development 2025; 152:dev204307. [PMID: 40110772 DOI: 10.1242/dev.204307] [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: 08/02/2024] [Accepted: 03/05/2025] [Indexed: 03/22/2025]
Abstract
Iron is essential for cell growth and hematopoiesis, which is regulated by hepcidin (hamp). However, the role of hamp in zebrafish hematopoiesis remains unclear. Here, we have created a stable hamp knockout zebrafish model using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease 9 system (CRISPR/Cas9 system). Our study revealed that hamp deletion led to maternal iron overload in embryos, significantly downregulating hemoglobin genes and reducing hemoglobin content. Single-cell RNA sequencing identified abnormal expression patterns in blood progenitor cells, with a specific progenitor subtype showing increased ferroptosis and delayed development. By crossing hamp knockout zebrafish with a gata1+ line (blood cells labeled fish line), we confirmed ferroptosis in blood progenitor cells. These findings underscore the crucial role of hamp in iron regulation and hematopoiesis, offering novel insights into developmental biology and potential therapeutic targets for blood disorders.
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Affiliation(s)
- Wenyi Yang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Mingjian Peng
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Youquan Wang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Xiaowen Zhang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Wei Li
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Xue Zhai
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Zhichao Wu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Peng Hu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Liangbiao Chen
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China
- International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
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17
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Appiah SK, Nkansah C, Appiah GA, Abbam G, Osei-Boakye F, Daud S, Mensah K, Adwoa S, Kuwaahsuore KS, Yeboah E, Tiyumba ASS, Thompson D, Paula VM, Duibajia LA, Takyia P, Kwarteng FA, Asiedu OO, Sukasorr FI, Kawuribi V, Ukwah BN, Chukwurah EF. Erythroferrone-Driven Regulation of Hepcidin and Iron Levels in Polytransfused Sickle Cell Anaemia Patients: A Prospective Study. BIOMED RESEARCH INTERNATIONAL 2025; 2025:6803051. [PMID: 40177293 PMCID: PMC11964725 DOI: 10.1155/bmri/6803051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 02/01/2025] [Indexed: 04/05/2025]
Abstract
The interplay of erythroferrone (ERFE), hepcidin, and ferroportin is crucial for ensuring systemic iron homeostasis. This study determined the influence of ERFE on hepcidin and iron levels in polytransfused patients with sickle cell anaemia (SCA). This multicentre case-control study recruited 60 SCA participants and 30 controls (HbA), aged 2-34 years, from Tamale Teaching Hospital; Methodist Hospital, Wenchi; and Seventh Day Adventist Hospital, Sunyani, Ghana, between the periods of March to July 2023. About 4 mL of blood was collected for a full blood count using a haematology analyzer and serum ERFE, hepcidin, ferroportin, and ferritin estimation using an enzyme-linked immunosorbent assay. Data were analyzed using SPSS Version 26.0. ERFE (p < 0.001), ferroportin (p = 0.016), ferritin (p < 0.001), serum iron (p < 0.001), transferrin (p = 0.001), soluble transferrin receptor (sTFR) (p = 0.019), TWBC (p < 0.001), and platelet (p < 0.001) were significantly higher in SCA participants and hydroxyurea-naïve participants than in the control group and hydroxyurea-treated participants, respectively. Levels of hepcidin (p < 0.001), red blood cell (p < 0.001), haemoglobin (p < 0.001), and haematocrit (p < 0.001) were lower in the SCA and hydroxyurea-naïve groups than in the control and hydroxyurea-treated groups, respectively. An inverse correlation was observed between serum ERFE and hepcidin (r = -0.391, p = 0.002) and hepcidin and ferroportin (r = -0.266, p = 0.040), while ferritin (r = 0.439, p < 0.001) and ferroportin (r = 0.309, p = 0.016) showed a positive correlation with ERFE. No correlation was found between serum hepcidin and ferritin levels (r = 0.025, p = 0.853). Again, participants with regular blood transfusions had significantly higher levels of ERFE (p < 0.001) and ferritin (p = 0.002) than those with rare and no transfusions per year. None of the SCA participants had done iron testing. In conclusion, the negative impact of ERFE on hepcidin levels may exacerbate the risk of iron burden, as evident by elevated iron levels in SCA patients and the need for regular monitoring of the iron status of polytransfused SCA patients.
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Affiliation(s)
- Samuel Kwasi Appiah
- Department of Haematology, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, Ebonyi State University, Abakaliki, Nigeria
| | - Charles Nkansah
- Department of Haematology, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, Ebonyi State University, Abakaliki, Nigeria
| | - Godfred Amoah Appiah
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Gabriel Abbam
- Department of Haematology, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Felix Osei-Boakye
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, Ebonyi State University, Abakaliki, Nigeria
- Department of Medical Laboratory Technology, Faculty of Applied Science and Technology, Sunyani Technical University, Sunyani, Ghana
| | - Samira Daud
- Department of Haematology, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Kofi Mensah
- Department of Haematology, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, Ebonyi State University, Abakaliki, Nigeria
| | - Safo Adwoa
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Korah Seedolf Kuwaahsuore
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Emmanuel Yeboah
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Abu Siraj Salma Tiyumba
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Dennis Thompson
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Viel Mary Paula
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Louis Adda Duibajia
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Peter Takyia
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Franklina Ataa Kwarteng
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Obed Odame Asiedu
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Firdaus Ibrahim Sukasorr
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Vincent Kawuribi
- Department of Biomedical Laboratory Sciences, School of Allied Health Sciences, University for Development Studies, Tamale, Ghana
| | - Boniface Nwofoke Ukwah
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, Ebonyi State University, Abakaliki, Nigeria
| | - Ejike Felix Chukwurah
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, Ebonyi State University, Abakaliki, Nigeria
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18
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Cao Y, Huang K, Luo J. Research on iron regulatory erythroid factors in children with β-thalassemia. J Investig Med 2025:10815589251331618. [PMID: 40103337 DOI: 10.1177/10815589251331618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
To investigate the differences in relative mRNA expression levels of the novel iron regulatory erythroid factors FAM210B, CCDC115, HO-1, PCBP1, PCBP2, NCOA4, and Nrf2 in children with β-thalassemia major (β-TM) before and after transfusion therapy. A total of 98 children with transfusion-dependent β-thalassemia were recruited from the First Affiliated Hospital of Guangxi Medical University between October 2022 and May 2023. The children were classified based on their hemoglobin (Hb) levels: 57 cases with Hb ≤ 90 g/L and 41 cases with Hb > 90 g/L. Real-time fluorescence quantitative PCR was employed to assess the relative mRNA expression between the groups. The mRNA expression levels of FAM210B, HO-1, and NCOA4 were significantly higher in the Hb ≤ 90 g/L group compared to the Hb > 90 g/L group (p < 0.05). Moreover, higher relative expression levels of FAM210B and NCOA4 correlated with an increased likelihood of requiring blood transfusions in β-TM children. The differences in the remaining factors did not reach statistical significance. FAM210B and NCOA4 may serve as indicators of erythropoiesis and the degree of anemia in children with β-TM. Further research is warranted to explore their potential as therapeutic targets for β-thalassemia and other erythropoietic disorders.
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Affiliation(s)
- Yaxuan Cao
- Department of Pediatrics, The First Affiliated Hospital Of Guangxi Medical University, Nanning, Guangxi, China
| | - Ken Huang
- Department of Pediatrics, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Jianming Luo
- Department of Pediatrics, The First Affiliated Hospital Of Guangxi Medical University, Nanning, Guangxi, China
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19
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Kouroumalis E, Tsomidis I, Voumvouraki A. HFE-Related Hemochromatosis May Be a Primary Kupffer Cell Disease. Biomedicines 2025; 13:683. [PMID: 40149659 PMCID: PMC11940282 DOI: 10.3390/biomedicines13030683] [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: 01/14/2025] [Revised: 02/28/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Iron overload can lead to increased deposition of iron and cause organ damage in the liver, the pancreas, the heart and the synovium. Iron overload disorders are due to either genetic or acquired abnormalities such as excess transfusions or chronic liver diseases. The most common genetic disease of iron deposition is classic hemochromatosis (HH) type 1, which is caused by mutations of HFE. Other rare forms of HH include type 2A with mutations at the gene hemojuvelin or type 2B with mutations in HAMP that encodes hepcidin. HH type 3, is caused by mutations of the gene that encodes transferrin receptor 2. Mutations of SLC40A1 which encodes ferroportin cause either HH type 4A or HH type 4B. In the present review, an overview of iron metabolism including absorption by enterocytes and regulation of iron by macrophages, liver sinusoidal endothelial cells (LSECs) and hepatocyte production of hepcidin is presented. Hereditary Hemochromatosis and the current pathogenetic model are analyzed. Finally, a new hypothesis based on published data was suggested. The Kupffer cell is the primary defect in HFE hemochromatosis (and possibly in types 2 and 3), while the hepcidin-relative deficiency, which is the common underlying abnormality in the three types of HH, is a secondary consequence.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete Medical School, 71500 Heraklion, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Greece;
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece;
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20
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Burke S, Chowdhury O, Rouault‐Pierre K. Low-risk MDS-A spotlight on precision medicine for SF3B1-mutated patients. Hemasphere 2025; 9:e70103. [PMID: 40124717 PMCID: PMC11926769 DOI: 10.1002/hem3.70103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/30/2025] [Accepted: 02/13/2025] [Indexed: 03/25/2025] Open
Abstract
A deep understanding of the biological mechanisms driving the pathogenesis of myelodysplastic neoplasms (MDS) is essential to develop comprehensive therapeutic approaches that will benefit patient's disease management and quality of life. In this review, we focus on MDS harboring mutations in the splicing factor SF3B1. Clones harboring this mutation arise from the most primitive hematopoietic compartment and expand throughout the entire myeloid lineage, exerting distinct effects at various stages of differentiation. Supportive care, particularly managing anemia, remains essential in SF3B1-mutated MDS. While SF3B1 mutations are frequently linked with ring sideroblasts and iron overload due to impaired erythropoiesis, the current therapeutic landscape fails to adequately address the underlying disease biology, particularly in transfusion-dependent patients, where further iron overload contributes to increased morbidity and mortality. Novel agents such as Luspatercept and Imetelstat have shown promise, but their availability remains restricted and their long-term efficacy is to be investigated. Spliceosome modulators have failed to deliver and inhibitors of inflammatory pathways, including TLR and NF-κB inhibitors, are still under investigation. This scarcity of effective and disease-modifying therapies highlights the unmet need for new approaches tailored to the molecular and genetic abnormalities in SF3B1-mutated MDS. Emerging strategies targeting metabolic mis-splicing (e.g., COASY) with vitamin B5, pyruvate kinase activators, and inhibitors of oncogenic pathways like MYC and BCL-2 represent potential future avenues for treatment, but their clinical utility remains to be fully explored. The current limitations in treatment underscore the urgency of developing novel, more effective therapies for patients with SF3B1-mutated MDS.
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Affiliation(s)
- Shoshana Burke
- Centre for Haemato‐OncologyBarts Cancer Institute, Queen Mary University of LondonLondonUK
| | - Onima Chowdhury
- Oxford University Hospitals NHS Foundation TrustOxfordUK
- Molecular Haematology Unit, Weatherall institute of Molecular Medicine NHR, Biomedical Research CentreUniversity of OxfordOxfordUK
| | - Kevin Rouault‐Pierre
- Centre for Haemato‐OncologyBarts Cancer Institute, Queen Mary University of LondonLondonUK
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21
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King RA, Khoriaty R. Hereditary disorders of ineffective erythropoiesis. Blood Cells Mol Dis 2025; 111:102910. [PMID: 39938185 PMCID: PMC11884990 DOI: 10.1016/j.bcmd.2025.102910] [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: 01/20/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
Under steady state conditions, humans must produce ∼2 million red blood cells per second to sustain normal red blood cell counts and hemoglobin levels. Ineffective erythropoiesis, also termed dyserythropoiesis, is a process by which erythroid precursors die or fail to efficiently differentiate in the bone marrow. Ineffective erythropoiesis is characterized by expanded bone marrow erythropoiesis and increased erythroferrone production by bone marrow erythroblasts, with the latter resulting in reduced hepcidin production and increased iron absorption. Ineffective erythropoiesis may result from acquired and congenital conditions. Inherited causes of ineffective erythropoiesis include β-thalassemia, sideroblastic anemias, pyruvate kinase deficiency, and congenital dyserythropoietic anemias. This manuscript reviews the definition and evidence for ineffective erythropoiesis and describes the most common hereditary disorders of dyserythropoiesis.
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MESH Headings
- Humans
- Erythropoiesis/genetics
- Anemia, Dyserythropoietic, Congenital/genetics
- Anemia, Dyserythropoietic, Congenital/pathology
- beta-Thalassemia/genetics
- beta-Thalassemia/pathology
- Anemia, Sideroblastic/genetics
- Anemia, Sideroblastic/pathology
- Pyruvate Metabolism, Inborn Errors/genetics
- Pyruvate Metabolism, Inborn Errors/pathology
- Pyruvate Kinase/deficiency
- Pyruvate Kinase/genetics
- Anemia, Hemolytic, Congenital Nonspherocytic
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Affiliation(s)
- Richard A King
- Department of Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA
| | - Rami Khoriaty
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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22
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Varghese J, Varghese JJ, Jacob M. Effect of a high-fat diet and iron overload on erythropoiesis in mice. Biochem Biophys Rep 2025; 41:101919. [PMID: 39980584 PMCID: PMC11841077 DOI: 10.1016/j.bbrep.2025.101919] [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: 10/25/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 02/22/2025] Open
Abstract
Background Insulin and iron availability stimulate and regulate erythropoiesis, respectively. The effects of hyperinsulinemia and/or iron overload on erythroid differentiation are unclear. Methodology Male C57Bl/6J wild-type (WT) mice were fed a high-fat diet (HFD) (to produce hyperinsulinemia) or a control diet (CD) for varying periods (4-24 weeks). Hepcidin knock-out (Hamp1 -/- ) mice (which are iron-overloaded) were fed CD or HFD for 24 weeks. Terminal erythroid differentiation (TED) in the bone marrow (BM) from these mice was analyzed by flow cytometry. Hematological parameters were estimated in peripheral blood. Results HFD-feeding of WT mice did not significantly affect erythroid precursors in the BM or hematological parameters. However, these mice had a significantly higher reticulocyte population in the BM than those fed CD (at all time points studied). Values of hematological parameters were higher in Hamp1 -/- mice than WT mice, at 24 weeks of feeding (irrespective of diet type), indicating increased erythropoiesis. Early erythroid precursors in the BM were higher in HFD-fed Hamp1 -/- mice than those fed CD. Conclusions HFD-feeding in WT mice resulted in increases in the proportion of reticulocytes in the bone marrow; maturation of the early erythroid precursors was not significantly affected. In Hamp1 -/- mice, HFD-feeding increased the number of early erythroid precursors.
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Affiliation(s)
- Joe Varghese
- Department of Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India1
| | - Jithu James Varghese
- Department of Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India1
| | - Molly Jacob
- Department of Biochemistry, Christian Medical College, Vellore, Tamil Nadu, India1
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23
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Blum S, Symeonidis A, Germing U. Editorial: MDS: new scientific and clinical developments. Front Oncol 2025; 15:1568681. [PMID: 40078185 PMCID: PMC11896990 DOI: 10.3389/fonc.2025.1568681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Affiliation(s)
- Sabine Blum
- Hematology Service and Central Laboratory of Hematology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Argiris Symeonidis
- Hematology Division, Department of Internal Medicine, University of Patras-School of Medicine, & Olympion General Clinic, Patras, Greece
| | - Ulrich Germing
- Department of Hematology, Oncology and Clinical Immunology, University Clinic, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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24
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Song J, Li N, Yang Y, Chen B, Hu J, Tian Y, Lin L, Qin Z. Cell-free hemoglobin released from hemolysis induces programmed cell death through iron overload and oxidative stress in grass carp (Ctenopharyngodon idella). FISH & SHELLFISH IMMUNOLOGY 2025; 157:110106. [PMID: 39755287 DOI: 10.1016/j.fsi.2024.110106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 12/22/2024] [Accepted: 12/29/2024] [Indexed: 01/06/2025]
Abstract
Intravascular hemolysis releases hemoglobin (Hb) from red blood cells under specific conditions, yet the effect of hemolysis in aquaculture systems remain poorly understood. In this study, a continuous hemolysis model for grass carp was established by injection of phenylhydrazine (PHZ) to investigate the mechanistic impacts of sustained hemolysis. PHZ-induced hemolysis altered liver color, and subsequent hematoxylin and eosin staining revealed substantial Hb accumulation in the head kidney, accompanied by inflammatory cell infiltration and vacuolization in liver tissue. Quantitative real-time PCR and western blotting confirmed that PHZ treatment significantly upregulated Real-time fluorescence quantitative PCR and Western blot confirmed that PHZ treatment significantly up-regulated the expression of iron metabolism-related genes and proteins, including transferrin (Tf), ferritin, ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), nuclear receptor coactivator 4 (NCOA4), divalent metal transporter 1 (DMT1), and six-transmembrane epithelial antigen of prostate 3 (STEAP3). Further investigation of PHZ-induced hemolysis effects on tissues showed that inflammation- and antioxidant enzyme-related genes in the liver and head kidney were significantly upregulated, indicating that hemolysis activated the antioxidant system and intensified inflammatory responses. Perls' staining revealed iron deposition in the head kidney and liver at ten and fourteen days post-PHZ injection. Moreover, β-galactosidase staining and transmission electron microscopy showed increased cellular senescence and mitochondrial damage, respectively, as a result of PHZ-induced hemolysis. In vitro assays with hemin treatment demonstrated increased Fe2+ content in CIK and L8824 cells, which induced oxidative stress, upregulated iron metabolism and inflammatory genes, and ultimately led to cell death. These findings suggest that excessive Hb release during sustained hemolysis leads to iron overload, elevates reactive oxygen species production, disrupts antioxidant balance, and ultimately causes cellular damage.
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Affiliation(s)
- Jialing Song
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Ningjing Li
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Yan Yang
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Bing Chen
- Laboratory of Animal Nutrition and Feed Science in South China, Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, China.
| | - Jiaxiang Hu
- SiChuan Water Conservancy Vocational College, Cheng Du, Si Chuan Province, 610000, China
| | - Ye Tian
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China
| | - Li Lin
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China.
| | - Zhendong Qin
- Guangdong Provincial Water Environment and Aquatic Products Security Engineering Technology Research Center, Guangzhou Key Laboratory of Aquatic Animal Diseases and Waterfowl Breeding, College of Animal Sciences and Technology, Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong Province, 510222, China.
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25
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Zhang DL, Ollivierre H, Qi CF, Rouault TA. A bulge uridine in the HIF2α IRE allows IRP1 but not IRP2 to selectively regulate HIF2α expression and ensuing EPO levels. Blood 2025; 145:533-542. [PMID: 39316647 PMCID: PMC11826522 DOI: 10.1182/blood.2024025246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 08/30/2024] [Accepted: 09/05/2024] [Indexed: 09/26/2024] Open
Abstract
ABSTRACT Iron regulatory proteins (IRP1 and IRP2) play a pivotal role in maintaining cellular iron homeostasis by binding to iron-responsive elements (IREs) of target messenger RNAs and regulating the expression of these iron-related genes. Mice and humans who lack functional IRP1 develop erythrocytosis due to erythropoietin (EPO) overproduction, whereas those who lack IRP2 develop microcytic anemia, believed to result from iron deficiency of erythroblasts. Here, we discovered that IRP2 deficiency reduced the expression of hypoxia-inducible factor 2α (HIF2α) and its transcriptional target, EPO, thereby compromising the stress erythropoiesis response to generate red blood cells upon anemia. The distinct consequences of IRP2 and IRP1 on EPO result from the higher binding affinity of the HIF2α IRE for IRP1 than IRP2. This difference in binding affinity arises from a bulge uridine in the upper stem of HIF2α IRE that impairs the ability of IRP2 to bind the IRE. These results reveal that IRP1 and IRP2 play distinct roles in erythropoiesis and unveil an unsuspected IRE binding preference that contributes to the divergent phenotypes observed in IRP1- and IRP2-deficient mammals.
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Affiliation(s)
- De-Liang Zhang
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Hayden Ollivierre
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Chen-Feng Qi
- Pathology Core, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Tracey A. Rouault
- Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
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26
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Leitch HA, Buckstein R. How I treat iron overload in adult MDS. Blood 2025; 145:383-396. [PMID: 38941618 DOI: 10.1182/blood.2023022501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/13/2024] [Accepted: 06/19/2024] [Indexed: 06/30/2024] Open
Abstract
ABSTRACT Although clinical benefits of iron chelation therapy (ICT) in red blood cell (RBC) transfusion-dependent (TD) hereditary anemias such as α-thalassemia major are incontrovertible, the evidence supporting a similar benefit in patients with TD myelodysplastic neoplasms (MDS) and iron overload (IOL) is sometimes debated. MDS presents later in life, has a limited repertoire of life-extending therapies, and patients may have comorbidities acting as competing causes of death. However, refined prognostication identifies patients with MDS with a reasonable life expectancy, and because 50% of patients will ultimately become RBC TD and develop transfusional IOL, ICT should be considered in some. Using illustrative cases, we summarize mechanisms of iron toxicity, strategies for the identification of IOL, and propose definitions of IOL severity. We provide rationale for, and recommend which patients may benefit from, ICT. We discuss currently available chelators, their administration, monitoring, side effects, and their management. Given challenges with the use of iron chelators, we suggest the nuances to be considered when planning chelation initiation to include the rate of iron accumulation, the presence of organ iron and/or dysfunction, and detectable indicators of oxidative stress. Areas for future investigation are identified.
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Affiliation(s)
- Heather A Leitch
- Division of Hematology, St Paul's Hospital and University of British Columbia, Vancouver, BC, Canada
| | - Rena Buckstein
- Division of Oncology/Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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27
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Qiu L, Frazer DM, Hu M, Song R, Liu X, Qin X, Ma J, Zhou J, Tan Z, Ren F, Collins JF, Wang X. Mechanism and regulation of iron absorption throughout the life cycle. J Adv Res 2025:S2090-1232(25)00002-5. [PMID: 39814221 DOI: 10.1016/j.jare.2025.01.002] [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: 10/26/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Iron plays a crucial role through various life stages of human. Iron homeostasis is primarily regulated by iron absorption which is mediated via divalent metal-ion transporter 1 (DMT1), and iron export protein ferroportin (FPN), as there is no active pathway for iron excretion from the body. Recent studies have shown that the magnitude of iron absorption changes through various life stages to meet changing iron requirements. AIM OF REVIEW This review aims to provide an overview of recent researches on the regulation of iron absorption throughout mammalian life cycle, with the potential to reveal novel molecules and pathways at special stage of life. Such insights may pave the way for new treatments for disorders associated with aberrant iron homeostasis in the future. KEY SCIENTIFIC CONCEPTS OF REVIEW This review first summarize the mechanism and regulation of iron absorption throughout various life stages, highlighting that regulatory mechanisms have developed to precisely align iron absorption to iron requirements. In adults, iron absorption is enhanced when body is deficient of iron, conversely, iron absorption is reduced when iron demand decreases via systemic regulator Hepcidin and cellular regulation. In the elderly, age-related inflammation, hormonal changes, and chronic diseases may affect the production of Hepcidin, affecting iron absorption. In infants, intestinal iron absorption and its regulatory mechanism are different from that in adults and there might be an alternative pathway independent of DMT1 and FPN due to high iron absorption. Unique to the fetus, iron is absorbed from maternal stores for its own use through the placenta and is regulated by maternal iron status. This review also proposes directions for further studies, offering promising avenues for developing new treatments for disorders associated with aberrant iron homeostasis.
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Affiliation(s)
- Lili Qiu
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - David M Frazer
- Molecular Nutrition Laboratory, QIMR Berghofer Medical Research Institute, Herston 4029 Australia
| | - Mengxiao Hu
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - Rui Song
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - Xiaoxue Liu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083 China
| | - Xiyu Qin
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - Jie Ma
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - Jun Zhou
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - Zidi Tan
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China
| | - Fazheng Ren
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China; Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083 China
| | - James F Collins
- Food Science & Human Nutrition Department, University of Florida, Gainesville, FL 32611, USA
| | - Xiaoyu Wang
- College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083 China; Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100083 China.
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Zhang L, Xu P, Yan X. Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Erythroferrone in Anemic Rats with Chronic Kidney Disease and Chemotherapy-Induced Anemia: An Early Biomarker for Hemoglobin Response and rHuEPO Hyporesponsiveness. ACS Pharmacol Transl Sci 2025; 8:189-202. [PMID: 39816799 PMCID: PMC11729431 DOI: 10.1021/acsptsci.4c00575] [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] [Received: 09/27/2024] [Revised: 11/20/2024] [Accepted: 11/29/2024] [Indexed: 01/18/2025]
Abstract
Erythroferrone (ERFE) has emerged as a potential biomarker for the erythropoiesis response following recombinant human erythropoietin (rHuEPO) treatment. While the association between ERFE and hemoglobin (HGB) response to rHuEPO is well-established in nonanemic conditions, such correlation and ERFE kinetics in anemic states remain unclear. We employed two rat models of anemia, chronic kidney disease (CKD) anemia and chemotherapy-induced anemia (CIA), to determine ERFE kinetics and its correlation with HGB responses after rHuEPO administration. The key factors influencing ERFE kinetics were characterized using a PK/PD modeling approach and supported by experimentation. Following rHuEPO injection, ERFE induction was diminished in anemic rats compared with that of healthy rats, primarily attributed to the reduced precursor cell mass and impaired rHuEPO responsiveness. The early increase in ERFE at 4 h post administration allows for the prompt prediction of HGB response and rHuEPO hyporesponsiveness in anemic rats. Consequently, the ERFE-based dose adjustment resulted in a rHuEPO-sparing effect in CKD rats. This strategy is expected to be translatable to anemic patients, potentially reducing rHuEPO doses and mitigating HGB overshooting.
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Affiliation(s)
- Lin Zhang
- Guangdong-Hong Kong-Macao
Joint Laboratory for New Drug Screening, School of Pharmacy, The Chinese University of Hong Kong, Shatin 999077, Hong Kong SAR, P.
R. China
| | - Peng Xu
- Guangdong-Hong Kong-Macao
Joint Laboratory for New Drug Screening, School of Pharmacy, The Chinese University of Hong Kong, Shatin 999077, Hong Kong SAR, P.
R. China
| | - Xiaoyu Yan
- Guangdong-Hong Kong-Macao
Joint Laboratory for New Drug Screening, School of Pharmacy, The Chinese University of Hong Kong, Shatin 999077, Hong Kong SAR, P.
R. China
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29
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Antypiuk A, Vance SZ, Sharma R, Passos S, Asperti M, Navaneethabalakrishan S, Dürrenberger F, Manolova V, Vinchi F. Genetic iron overload aggravates, and pharmacological iron restriction improves, MDS pathophysiology in a preclinical study. Blood 2025; 145:155-169. [PMID: 39437711 DOI: 10.1182/blood.2024026135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 10/25/2024] Open
Abstract
ABSTRACT Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation of ferroportin (FPN) via the C326S mutation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter FPN, respectively, in a MDS mouse model. Although FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated, and restriction alleviated, reactive oxygen species formation, DNA damage, and cell death in hematopoietic stem and progenitor cells (HSPCs), resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared with single treatments and offers additive beneficial effects in MDS. Our results prove, to our knowledge, for the first time in a preclinical model, that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.
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Affiliation(s)
- Ada Antypiuk
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - S Zebulon Vance
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - Richa Sharma
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - Sara Passos
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
| | - Michela Asperti
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | | | | | - Francesca Vinchi
- Iron Research Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
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30
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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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31
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Boucher AA, Dayton VJ, Pratt AR, Nassar NN, Elgammal Y, Kalfa TA. Three-generation female cohort with macrocytic anemia and iron overload. Am J Hematol 2025; 100:133-138. [PMID: 39329459 PMCID: PMC11625981 DOI: 10.1002/ajh.27489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 09/02/2024] [Accepted: 09/12/2024] [Indexed: 09/28/2024]
Affiliation(s)
- Alexander A. Boucher
- Division of Pediatric Hematology/Oncology, Department of PediatricsUniversity of MinnesotaMinneapolisMinnesotaUSA
- Division of Hematology, Oncology, and Transplantation, Department of MedicineUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Vanessa J. Dayton
- Laboratory Medicine and Pathology, Hennepin County Medical CenterHennepin Healthcare Research InstituteMinneapolisMinnesotaUSA
| | - Annaliisa R. Pratt
- Laboratory Medicine and Pathology, Hennepin County Medical CenterHennepin Healthcare Research InstituteMinneapolisMinnesotaUSA
| | - Nicolas N. Nassar
- Cancer and Blood Diseases InstituteCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
- Department of PediatricsUniversity of Cincinnati Medical SchoolCincinnatiOhioUSA
| | - Yasmin Elgammal
- Cancer and Blood Diseases InstituteCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Theodosia A. Kalfa
- Cancer and Blood Diseases InstituteCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
- Department of PediatricsUniversity of Cincinnati Medical SchoolCincinnatiOhioUSA
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32
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McMartin MC, Savkovic S, Romano A, Lim S, Muir CA, Jayadev V, Conway AJ, Seccombe L, Handelsman DJ. Testosterone and Erythrocyte Lifespan. J Clin Endocrinol Metab 2024; 110:114-122. [PMID: 38912796 DOI: 10.1210/clinem/dgae434] [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: 04/30/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
CONTEXT Endogenous and exogenous androgens increase circulating erythrocytes and hemoglobin but their effects on erythrocyte lifespan is not known. OBJECTIVE To investigate androgen effects on immature and mature erythrocyte lifespan in humans and mice using novel nonradioactive minimally invasive methods. DESIGN Human erythrocyte lifespan was estimated using alveolar carbon monoxide concentration and blood hemoglobin in Levitt's formula in hypogonadal or transgender men before and up to 18 weeks after commencing testosterone (T) treatment. Erythrocyte lifespan was estimated in androgen receptor knockout and wild-type mice after T or DHT treatment of intact females or orchidectomized males using in vivo biotin labelling of erythrocyte surface epitopes for reticulocytes (Ter119+CD71+) and 2 markers of erythrocytes (CD45-, Ter119+CD71-) monitoring their blood disappearance rate by flow cytometry. RESULTS Before treatment, hypogonadal and transgender men had marked reduction in erythrocyte lifespan compared with controls. T treatment increased erythrocyte lifespan at 6 weeks but returned to pretreatment levels at 18 weeks, whereas serum T and blood hemoglobin were increased by T treatment remaining elevated at 18 weeks. In mice, T and DHT treatment had higher erythrocyte (but not reticulocyte) lifespan but neither orchidectomy nor androgen receptor inactivation significantly influenced erythrocyte or reticulocyte lifespan. CONCLUSION We conclude that hypogonadal men have reduced erythrocyte lifespan and acute androgen-induced increase in circulating erythrocyte lifespan may contribute to the well-known erythropoietic effects of androgens, but longer term effects require further investigation to determine how much they contribute to androgen-induced increases in circulating hemoglobin.
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Affiliation(s)
- Melissa C McMartin
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
| | - Sasha Savkovic
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Adelina Romano
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
| | - Sarina Lim
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Christopher A Muir
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Veena Jayadev
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Ann J Conway
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - Leigh Seccombe
- Respiratory Medicine Department, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
| | - David J Handelsman
- ANZAC Research Institute, University of Sydney, Concord Repatriation General Hospital, Concord Hospital, Sydney, NSW 2139, Australia
- Andrology, Concord Repatriation General Hospital Concord Hospital, Sydney, NSW 2139, Australia
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33
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Czaya B, Olivera JD, Zhang M, Lundin A, Castro CD, Jung G, Nemeth E, Ganz T. Transgenic augmentation of erythroferrone in mice ameliorates anemia in adenine-induced chronic kidney disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.06.627111. [PMID: 39713359 PMCID: PMC11661078 DOI: 10.1101/2024.12.06.627111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Anemia is a common and disabling complication of chronic kidney disease (CKD). Current therapies can be burdensome, and full correction of anemia is limited by cardiovascular side effects. New approaches that may offer additional therapeutic options are needed. We explored the anti-anemic effects of erythroferrone, an erythroid hormone that induces iron mobilization by suppressing the master iron-regulatory hormone hepcidin. In a preclinical murine model of adenine-induced CKD, transgenic augmentation of erythroferrone mobilized iron, increased hemoglobin concentrations by approximately 2 g/dl, and modestly improved renal function without affecting systemic or renal inflammation, fibrosis, or markers of mineral metabolism. This study supports the concept that therapeutic augmentation of erythroferrone is a promising approach for alleviating CKD-associated anemia.
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Affiliation(s)
- Brian Czaya
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Joseph D Olivera
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Moya Zhang
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Amber Lundin
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Christian D Castro
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Grace Jung
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Elizabeta Nemeth
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
| | - Tomas Ganz
- Center for Iron Disorders, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, CA 90095-1690
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34
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Gattermann N. Iron overload in acquired sideroblastic anemias and MDS: pathophysiology and role of chelation and luspatercept. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:443-449. [PMID: 39644054 DOI: 10.1182/hematology.2024000569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Besides transfusion therapy, ineffective erythropoiesis contributes to systemic iron overload in myelodysplastic syndromes with ring sideroblasts (MDS-RS) via erythroferrone-induced suppression of hepcidin synthesis in the liver, leading to increased intestinal iron absorption. The underlying pathophysiology of MDS-RS, characterized by disturbed heme synthesis and mitochondrial iron accumulation, is less well understood. Several lines of evidence indicate that the mitochondrial transporter ABCB7 is critically involved. ABCB7 is misspliced and underexpressed in MDS-RS, due to somatic mutations in the splicing factor SF3B1. The pathogenetic significance of ABCB7 seems related to its role in stabilizing ferrochelatase, the enzyme incorporating iron into protoporphyrin IX to make heme. Although iron-related oxidative stress is toxic, many patients with MDS do not live long enough to develop clinical complications of iron overload. Furthermore, it is difficult to determine the extent to which iron overload contributes to morbidity and mortality in older patients with MDS, because iron-related complications overlap with age-related medical problems. Nevertheless, high-quality registry studies showed that transfusion dependency is associated with the presence of toxic iron species and inferior survival and confirmed a significant survival benefit of iron chelation therapy. The most widely used iron chelator in patients with MDS is deferasirox, owing to its effectiveness and convenient oral administration. Luspatercept, which can reduce SMAD2/SMAD3-dependent signaling implicated in suppression of erythropoiesis, may obviate the need for red blood cell transfusion in MDS-RS for more than a year, thereby diminishing further iron loading. However, luspatercept cannot be expected to substantially reduce the existing iron overload.
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35
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Medjbeur T, Personnaz J, Kautz L. [FGL1 : a new target for the treatment of anemia ?]. Med Sci (Paris) 2024; 40:722-724. [PMID: 39450956 DOI: 10.1051/medsci/2024123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2024] Open
Affiliation(s)
- Thanina Medjbeur
- IRSD, Université de Toulouse, Inserm, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS) Toulouse France
| | - Jean Personnaz
- IRSD, Université de Toulouse, Inserm, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS) Toulouse France
| | - Léon Kautz
- IRSD, Université de Toulouse, Inserm, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS) Toulouse France
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36
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Mendoza E, Duque X, Reyes-Maldonado E, Hernández-Franco JI, Martínez-Andrade G, Vilchis-Gil J, Martinez H, Morán S. Serum hepcidin recalibrated values in Mexican schoolchildren by demographic characteristics, nutritional and infection/inflammation status. Ann Hematol 2024; 103:3979-3986. [PMID: 39039174 DOI: 10.1007/s00277-024-05889-4] [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: 02/28/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024]
Abstract
Hepcidin production is regulated by iron concentration, erythropoietic activity, and inflammation. There is no reference method for determining its levels, but results obtained through various methods strongly correlate and can be compared using recalibration equations. OBJECTIVE To describe recalibrated serum hepcidin values at different percentiles in schoolchildren, considering age, sex, inflammatory processes, H. pylori infection, and iron status. METHODS Secondary analysis of data incorporating information on inflammation, H. pylori infection, and iron status of 349 schoolchildren. Hepcidin analysis was performed using a competitive ELISA, and recalibrated hepcidin values were calculated using the inverse of the linear regression model equation obtained by van der Vorm et al. Results: Recalibrated hepcidin values were lower than non-calibrated values. In schoolchildren without infection/inflammation and without iron deficiency, recalibrated values at the 50th percentile (25th-75th) were 4.89 ng/mL (2.68-8.42). For schoolchildren without infection/inflammation but with iron deficiency, recalibrated values were 2.34 ng/mL (1.10-6.58), the lowest hepcidin values observed. The highest values were found in the group with infection/inflammation, regardless of iron deficiency status. CONCLUSIONS Recalibrated hepcidin values were lower than non-calibrated values. The highest values were observed in schoolchildren with infectious or inflammatory processes, and the lowest values were observed in schoolchildren with iron deficiency but only in the absence of infectious or inflammatory processes. Using recalibrated hepcidin values allows comparison between data obtained using different analytical methods.
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Affiliation(s)
- Eugenia Mendoza
- Infectious Diseases Research Unit, Mexican Social Security Institute, Av. Cuauhtemoc No. 330, Col. Doctores, Del. Cuauhtemoc, Mexico City, CP 06720, Mexico
| | - Ximena Duque
- Infectious Diseases Research Unit, Mexican Social Security Institute, Av. Cuauhtemoc No. 330, Col. Doctores, Del. Cuauhtemoc, Mexico City, CP 06720, Mexico.
| | - Elba Reyes-Maldonado
- Department of Hematopathology, National Polytechnic Institute, National School of Biological Sciences, Mexico City, 01135, Mexico
| | | | - Gloria Martínez-Andrade
- Academic Area of Nutrition, Institute of Health Sciences, Autonomous University of the State of Hidalgo, Pachuca Hidalgo, 42039, Mexico
| | - Jenny Vilchis-Gil
- Hospital Infantil de México "Federico Gomez", Mexico City, 06720, Mexico
| | - Homero Martinez
- Hospital Infantil de México "Federico Gomez", Mexico City, 06720, Mexico
- Global Technical Services-NTEAM, Nutrition International, Ottawa, ON, K2P 2K3, Canada
| | - Segundo Morán
- Gastroenterology Research Laboratory, Mexican Social Security Institute, Mexico City, 06720, Mexico
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37
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Maltaneri RE, Chamorro ME, Gionco SE, Nesse AB, Vittori DC. Erythropoietin enhances iron bioavailability in HepG2 cells by downregulating hepcidin through mTOR, C/EBPα and HIF-1α. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119800. [PMID: 39047915 DOI: 10.1016/j.bbamcr.2024.119800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 06/26/2024] [Accepted: 07/12/2024] [Indexed: 07/27/2024]
Abstract
The regulation of iron (Fe) levels is essential to maintain an adequate supply for erythropoiesis, among other processes, and to avoid possible toxicity. The liver-produced peptide hepcidin is regarded as the main regulator of Fe absorption in enterocytes and release from hepatocytes and macrophages, as it impairs Fe export through ferroportin. The glycoprotein erythropoietin (Epo) drives erythroid progenitor survival and differentiation in the bone marrow, and has been linked to the mobilization of Fe reserves necessary for hemoglobin production. Herein we show that Epo inhibits hepcidin expression directly in the HepG2 hepatic cell line, thus leading to a decrease in intracellular Fe levels. Such inhibition was dependent on the Epo receptor-associated kinase JAK2, as well as on the PI3K/AKT/mTOR pathway, which regulates nutrient homeostasis. Epo was also found to decrease binding of the C/EBP-α transcription factor to the hepcidin promoter, which could be attributed to an increased expression of its inhibitor CHOP. Epo did not only hinder the stimulating effect of C/EBP-α on hepcidin transcription, but also favored hepcidin inhibition by HIF-1α, by increasing is nuclear translocation as well as its protein levels. Moreover, in assays with the inhibitor genistein, this transcription factor was found necessary for Epo-induced hepcidin suppression. Our findings support the involvement of the PI3K/AKT/mTOR pathway in the regulation of Fe levels by Epo, and highlight the contrasting roles of the C/EBP-α and HIF-1α transcription factors as downstream effectors of the cytokine in this process.
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Affiliation(s)
- Romina Eugenia Maltaneri
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina.
| | - María Eugenia Chamorro
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Silvana Estela Gionco
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Alcira Beatriz Nesse
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
| | - Daniela Cecilia Vittori
- Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto del Departamento de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
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38
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Babar S, Saboor M. Erythroferrone in focus: emerging perspectives in iron metabolism and hematopathologies. BLOOD SCIENCE 2024; 6:e00198. [PMID: 39027903 PMCID: PMC11254117 DOI: 10.1097/bs9.0000000000000198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 06/25/2024] [Indexed: 07/20/2024] Open
Abstract
Beyond its core role in iron metabolism, erythroferrone (ERFE) has emerged as a key player with far-reaching implications in various hematologic disorders. Its regulatory effect on hepcidin underlines its significance in conditions characterized by disrupted iron homeostasis. In β-thalassemia and myelodysplastic syndromes, its dysregulation intricately contributes to the clinical challenges of anemia and iron overload which highlights its potential as a therapeutic target. In anemia of chronic disease and iron deficiency anemia, ERFE presents a unique profile. In chronic kidney disease (CKD), the intricate interplay between ERFE, erythropoietin, and hepcidin undergoes dysregulation, contributing to the complex iron imbalance characteristic of this condition. Recent research suggests that ERFE plays a multifaceted role in restoring iron balance in CKD, beyond simply suppressing hepcidin production. The potential to modulate ERFE activity offers a novel approach to treating a spectrum of disorders associated with iron dysregulation. As our understanding of ERFE continues to evolve, it is poised to become a key focus in the development of targeted treatments, making it an exciting and dynamic area of ongoing research. Modulating ERFE activity presents a groundbreaking approach to treat iron dysregulation in conditions like iron deficiency anemia, thalassemia, and hemochromatosis. As new research unveils its intricate roles, ERFE has rapidly emerged as a key target for developing targeted therapies like ERFE agonists and antagonists. With promising studies underway, this dynamic field holds immense potential to improve patient outcomes, reduce complications, and offer personalized treatment options in hematology research. This comprehensive overview of ERFE's role across various conditions underscores its pivotal function in iron metabolism and associated pathologies.
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Affiliation(s)
- Sadia Babar
- Baqai Institute of Hematology, Baqai Medical University, Karachi, Pakistan
- Baqai Institute of Medical Technology, Baqai Medical University, Karachi, Pakistan
| | - Muhammad Saboor
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
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Pilo F, Angelucci E. Vamifeport: Monography of the First Oral Ferroportin Inhibitor. J Clin Med 2024; 13:5524. [PMID: 39337010 PMCID: PMC11432582 DOI: 10.3390/jcm13185524] [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: 08/15/2024] [Revised: 09/07/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Over the last few years, several mechanisms that are involved in congenital diseases characterized by ineffective erythropoiesis have been described. Therefore, multiple new target drugs are being developed in preclinical models against the main regulators of normal erythropoiesis. Above all, the key mechanism that regulates systemic iron homeostasis, represented by the hepcidin-ferroportin axis, is considered to be the target for new therapies. The main hypothesis is that iron restriction, through blocking ferroportin (the unique iron transporter in mammals) in such diseases, ameliorates erythropoiesis. The action of vamifeport is different from the currently approved drugs in this setting since it acts straight on the ferroportin-hepcidin axis. The data presented in the sickle cell disease (SCD) Townes mouse model showed a preclinical proof-of-concept for the efficacy of oral ferroportin inhibitor. Vamifeport reduced hemoglobin concentration in red blood cells (RBCs) and diminished intravascular hemolysis and inflammation, improving hemodynamics and preventing vascular occlusive crises. On this basis, clinical trials were commenced in patients with SCD, non-transfusion-dependent (NTD) thalassemia and transfusion-dependent (TD) thalassemia. Preliminary data in NTD thalassemic patients also confirm the safety and efficacy in decreasing iron level. In conclusion, vamifeport represents a new option in the panorama of drugs targeting the hepcidin-ferroportin axis, but its efficacy is still under investigation as a single agent.
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Affiliation(s)
- Federica Pilo
- Hematology and Transplant Center, Azienda Ospedaliera Brotzu, 09121 Cagliari, Italy
| | - Emanuele Angelucci
- Hematology and Cellular Therapy Center, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
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40
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Nazarov K, Perik-Zavodskii R, Perik-Zavodskaia O, Alrhmoun S, Volynets M, Shevchenko J, Sennikov S. Acute blood loss in mice forces differentiation of both CD45-positive and CD45-negative erythroid cells and leads to a decreased CCL3 chemokine production by bone marrow erythroid cells. PLoS One 2024; 19:e0309455. [PMID: 39231178 PMCID: PMC11373861 DOI: 10.1371/journal.pone.0309455] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/09/2024] [Indexed: 09/06/2024] Open
Abstract
Hemorrhage, a condition that accompanies most physical trauma cases, remains an important field of study, a field that has been extensively studied in the immunological context for myeloid and lymphoid cells, but not as much for erythroid cells. In this study, we studied the immunological response of murine erythroid cells to acute blood loss using flow cytometry, NanoString immune transcriptome profiling, and BioPlex cytokine secretome profiling. We observed that acute blood loss forces the differentiation of murine erythroid cells in both bone marrow and spleen and that there was an up-regulation of several immune response genes, in particular pathogen-associated molecular pattern sensing gene Clec5a in post-acute blood loss murine bone marrow erythroid cells. We believe that the up-regulation of the Clec5a gene in bone marrow erythroid cells could help bone marrow erythroid cells detect and eliminate pathogens with the help of reactive oxygen species and antimicrobial proteins calprotectin and cathelicidin, the genes of which (S100a8, S100a9, and Camp) dominate the expression in bone marrow erythroid cells of mice.
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Affiliation(s)
- Kirill Nazarov
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Roman Perik-Zavodskii
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Olga Perik-Zavodskaia
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Saleh Alrhmoun
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Marina Volynets
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Julia Shevchenko
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | - Sergey Sennikov
- Laboratory of molecular immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
- Department of Immunology, Zelman Institute for Medicine and Psychology, Novosibirsk State University, Novosibirsk, Russia
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41
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Musallam KM, Sheth S, Cappellini MD, Forni GL, Maggio A, Taher AT. Anemia and iron overload as prognostic markers of outcomes in β-thalassemia. Expert Rev Hematol 2024; 17:631-642. [PMID: 39037857 DOI: 10.1080/17474086.2024.2383420] [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: 06/04/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Ineffective erythropoiesis and subsequent anemia as well as primary and secondary (transfusional) iron overload are key drivers for morbidity and mortality outcomes in patients with β-thalassemia. AREAS COVERED In this review, we highlight evidence from observational studies evaluating the association between measures of anemia and iron overload versus outcomes in both non-transfusion-dependent and transfusion-dependent forms of β-thalassemia. EXPERT OPINION Several prognostic thresholds have been identified with implications for patient management. These have also formed the basis for the design of novel therapy clinical trials by informing eligibility and target endpoints. Still, several data gaps persist in view of the challenge of assessing prospective long-term outcomes in a chronic disease. Pooling insights on the prognostic value of different measures of disease mechanism will be key to design future scoring systems that can help optimize patient management.
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Affiliation(s)
- Khaled M Musallam
- Center for Research on Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, United Arab Emirates
- Division of Hematology/Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
| | - Sujit Sheth
- Division of Hematology/Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA
| | - Maria Domenica Cappellini
- Department of Clinical Sciences and Community, University of Milan, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, Italy
| | | | - Aurelio Maggio
- Campus of Haematology Franco and Piera Cutino, AOOR Villa Sofia-V. Cervello, Palermo, Italy
| | - Ali T Taher
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Pinto VM, Mazzi F, De Franceschi L. Novel therapeutic approaches in thalassemias, sickle cell disease, and other red cell disorders. Blood 2024; 144:853-866. [PMID: 38820588 DOI: 10.1182/blood.2023022193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 05/16/2024] [Accepted: 05/19/2024] [Indexed: 06/02/2024] Open
Abstract
ABSTRACT In this last decade, a deeper understanding of the pathophysiology of hereditary red cell disorders and the development of novel classes of pharmacologic agents have provided novel therapeutic approaches to thalassemias, sickle cell disease (SCD), and other red cell disorders. Here, we analyze and discuss the novel therapeutic options according to their targets, taking into consideration the complex process of erythroid differentiation, maturation, and survival of erythrocytes in the peripheral circulation. We focus on active clinical exploratory and confirmatory trials on thalassemias, SCD, and other red cell disorders. Beside β-thalassemia and SCD, we found that the development of new therapeutic strategies has allowed for the design of clinic studies for hereditary red cell disorders still lacking valuable therapeutic alternative such as α-thalassemias, congenital dyserythropoietic anemia, or Diamond-Blackfan anemia. In addition, reduction of heme synthesis, which can be achieved by the repurposed antipsychotic drug bitopertin, might affect not only hematological disorders but multiorgan diseases such as erythropoietic protoporphyria. Finally, our review highlights the current state of therapeutic scenarios, in which multiple indications targeting different red cell disorders are being considered for a single agent. This is a welcome change that will hopefully expand therapeutic option for patients affected by thalassemias, SCD, and other red cell disorders.
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Affiliation(s)
- Valeria Maria Pinto
- Ematologia e Terapie Cellulari, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Centro della Microcitemia, Anemie Congenite e Dismetabolismo del Ferro, Ente Ospedaliero Ospedali Galliera, Genoa, Italy
| | - Filippo Mazzi
- Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Lucia De Franceschi
- Department of Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
- Department of Engineering for Innovative Medicine, University of Verona, Verona, Italy
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43
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Zhao Y, Zhu L, Shi D, Gao J, Fan M. Key Genes FECH and ALAS2 under Acute High-Altitude Exposure: A Gene Expression and Network Analysis Based on Expression Profile Data. Genes (Basel) 2024; 15:1075. [PMID: 39202434 PMCID: PMC11353374 DOI: 10.3390/genes15081075] [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: 07/15/2024] [Revised: 08/08/2024] [Accepted: 08/11/2024] [Indexed: 09/03/2024] Open
Abstract
High-altitude acclimatization refers to the physiological adjustments and adaptation processes by which the human body gradually adapts to the hypoxic conditions of high altitudes after entering such environments. This study analyzed three mRNA expression profile datasets from the GEO database, focusing on 93 healthy residents from low altitudes (≤1400 m). Peripheral blood samples were collected for analysis on the third day after these individuals rapidly ascended to higher altitudes (3000-5300 m). The analysis identified significant differential expression in 382 genes, with 361 genes upregulated and 21 downregulated. Further, gene ontology (GO) annotation analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that the top-ranked enriched pathways are upregulated, involving blood gas transport, erythrocyte development and differentiation, and heme biosynthetic process. Network analysis highlighted ten key genes, namely, SLC4A1, FECH, EPB42, SNCA, GATA1, KLF1, GYPB, ALAS2, DMTN, and GYPA. Analysis revealed that two of these key genes, FECH and ALAS2, play a critical role in the heme biosynthetic process, which is pivotal in the development and maturation of red blood cells. These findings provide new insights into the key gene mechanisms of high-altitude acclimatization and identify potential biomarkers and targets for personalized acclimatization strategies.
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Affiliation(s)
- Yifan Zhao
- School of Information Science and Engineering, Lanzhou University, Lanzhou 730000, China;
| | - Lingling Zhu
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China;
| | - Dawei Shi
- School of Automation, Beijing Institute of Technology, Beijing 100850, China;
| | - Jiayue Gao
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China;
| | - Ming Fan
- School of Information Science and Engineering, Lanzhou University, Lanzhou 730000, China;
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Zhang H, Liu R, Fang Z, Nie L, Ma Y, Sun F, Mei J, Song Z, Ginzburg YZ, Liu J, Chen H. Mitoxantrone ameliorates ineffective erythropoiesis in a β-thalassemia intermedia mouse model. Blood Adv 2024; 8:4017-4024. [PMID: 38861356 PMCID: PMC11339037 DOI: 10.1182/bloodadvances.2024012679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 05/15/2024] [Accepted: 06/03/2024] [Indexed: 06/13/2024] Open
Abstract
ABSTRACT β-thalassemia is a condition characterized by reduced or absent synthesis of β-globin resulting from genetic mutations, leading to expanded and ineffective erythropoiesis. Mitoxantrone has been widely used clinically as an antitumor agent considering its ability to inhibit cell proliferation. However, its therapeutic effect on expanded and ineffective erythropoiesis in β-thalassemia is untested. We found that mitoxantrone decreased α-globin precipitates and ameliorated anemia, splenomegaly, and ineffective erythropoiesis in the HbbTh3/+ mouse model of β-thalassemia intermedia. The partially reversed ineffective erythropoiesis is a consequence of effects on autophagy as mitochondrial retention and protein levels of mTOR, P62, and LC3 in reticulocytes decreased in mitoxantrone-treated HbbTh3/+ mice. These data provide significant preclinical evidence for targeting autophagy as a novel therapeutic approach for β-thalassemia.
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Affiliation(s)
- Haihang Zhang
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
| | - Rui Liu
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
| | - Zheng Fang
- College of Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Ling Nie
- Xiangya Hospital, Central South University, Changsha, China
| | - Yanlin Ma
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
| | - Fei Sun
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
| | - Jingjing Mei
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
| | - Zhiyin Song
- College of Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yelena Z. Ginzburg
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jing Liu
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
| | - Huiyong Chen
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
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45
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Xu P, Wong RSM, Yan X. Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents. Br J Pharmacol 2024; 181:2833-2850. [PMID: 38653449 DOI: 10.1111/bph.16396] [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: 09/18/2023] [Revised: 03/15/2024] [Accepted: 03/17/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND AND PURPOSE Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. EXPERIMENTAL APPROACH By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. KEY RESULTS The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. CONCLUSIONS AND IMPLICATIONS The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.
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Affiliation(s)
- Peng Xu
- School of Pharmacy, The Chinese University of Hong Kong, HKSAR, China
- Phase I Clinical Trial Center, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Raymond S M Wong
- Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiaoyu Yan
- School of Pharmacy, The Chinese University of Hong Kong, HKSAR, China
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Stankiewicz B, Mieszkowski J, Kochanowicz A, Brzezińska P, Niespodziński B, Kowalik T, Waldziński T, Kowalski K, Borkowska A, Reczkowicz J, Daniłowicz-Szymanowicz L, Antosiewicz J. Effect of Single High-Dose Vitamin D 3 Supplementation on Post-Ultra Mountain Running Heart Damage and Iron Metabolism Changes: A Double-Blind Randomized Controlled Trial. Nutrients 2024; 16:2479. [PMID: 39125358 PMCID: PMC11313756 DOI: 10.3390/nu16152479] [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: 07/10/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Exercise-induced inflammation can influence iron metabolism. Conversely, the effects of vitamin D3, which possesses anti-inflammatory properties, on ultramarathon-induced heart damage and changes in iron metabolism have not been investigated. Thirty-five healthy long-distance semi-amateur runners were divided into two groups: one group received 150,000 IU of vitamin D3 24 h prior to a race (n = 16), while the other group received a placebo (n = 19). Serum iron, hepcidin (HPC), ferritin (FER), erythroferrone (ERFE), erythropoietin (EPO), neopterin (NPT), and cardiac troponin T (cTnT) levels were assessed. A considerable effect of ultramarathon running on all examined biochemical markers was observed, with a significant rise in serum levels of ERFE, EPO, HPC, NPT, and cTnT detected immediately post-race, irrespective of the group factor. Vitamin D3 supplementation showed a notable interaction with the UM, specifically in EPO and cTnT, with no other additional changes in the other analysed markers. In addition to the correlation between baseline FER and post-run ERFE, HPC was modified by vitamin D. The ultramarathon significantly influenced the EPO/ERFE/HPC axis; however, a single substantial dose of vitamin D3 had an effect only on EPO, which was associated with the lower heart damage marker cTnT after the run.
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Affiliation(s)
- Błażej Stankiewicz
- Department of Theory and Methodology of Physical Education and Sport, Faculty of Health Sciences and Physical Education, Kazimierz Wielki University, 85-064 Bydgoszcz, Poland; (B.S.); (T.K.)
| | - Jan Mieszkowski
- Department of Gymnastics and Dance, Gdańsk University of Physical Education and Sport, 80-336 Gdańsk, Poland; (A.K.); (P.B.)
- Faculty of Physical Education and Sport, Charles University, 16-252 Prague, Czech Republic
| | - Andrzej Kochanowicz
- Department of Gymnastics and Dance, Gdańsk University of Physical Education and Sport, 80-336 Gdańsk, Poland; (A.K.); (P.B.)
| | - Paulina Brzezińska
- Department of Gymnastics and Dance, Gdańsk University of Physical Education and Sport, 80-336 Gdańsk, Poland; (A.K.); (P.B.)
| | - Bartłomiej Niespodziński
- Department of Biological Foundations of Physical Education, Faculty of Health Sciences and Physical Education, Kazimierz Wielki University, 85-064 Bydgoszcz, Poland;
| | - Tomasz Kowalik
- Department of Theory and Methodology of Physical Education and Sport, Faculty of Health Sciences and Physical Education, Kazimierz Wielki University, 85-064 Bydgoszcz, Poland; (B.S.); (T.K.)
| | - Tomasz Waldziński
- Faculty of Health Sciences, University of Lomza, 18-400 Łomża, Poland;
| | - Konrad Kowalski
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdańsk, 80-211 Gdańsk, Poland; (K.K.); (A.B.); (J.R.)
| | - Andżelika Borkowska
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdańsk, 80-211 Gdańsk, Poland; (K.K.); (A.B.); (J.R.)
| | - Joanna Reczkowicz
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdańsk, 80-211 Gdańsk, Poland; (K.K.); (A.B.); (J.R.)
| | | | - Jędrzej Antosiewicz
- Department of Bioenergetics and Physiology of Exercise, Medical University of Gdańsk, 80-211 Gdańsk, Poland; (K.K.); (A.B.); (J.R.)
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Glenthøj A, van Beers EJ, van Wijk R, Rab MAE, Groot E, Vejlstrup N, Toft N, Bendtsen SK, Petersen J, Helby J, Chermat F, Fenaux P, Kuo KHM. Designing a single-arm phase 2 clinical trial of mitapivat for adult patients with erythrocyte membranopathies (SATISFY): a framework for interventional trials in rare anaemias - pilot study protocol. BMJ Open 2024; 14:e083691. [PMID: 39079928 PMCID: PMC11293418 DOI: 10.1136/bmjopen-2023-083691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 07/12/2024] [Indexed: 08/03/2024] Open
Abstract
INTRODUCTION Membranopathies encompass haemolytic disorders arising from genetic variants in erythrocyte membrane proteins, including hereditary spherocytosis and stomatocytosis. Congenital dyserythropoietic anaemia type II (CDA II) is associated with the SEC23B gene and can exhibit phenotypic similarities to membranopathies. Current treatment options for these conditions, apart from splenectomy, are primarily supportive. Mitapivat, a novel pyruvate kinase (PK) activator, has demonstrated efficacy in increasing haemoglobin levels and reducing haemolysis in patients with PK deficiency, thalassemia, sickle cell disease and a mouse model of hereditary spherocytosis. METHODS AND ANALYSES Safety and efficacy of mitapivat sulfate in adult patients with erythrocyte membranopathies (SATISFY) is a prospective, multicentre, single-arm phase two trial involving approximately 25 adult patients (≥18 years) diagnosed with a membranopathy or CDA II. During the 8-week dose escalation period, subjects will receive an initial dose of 50 mg mitapivat two times per day and may increase to 100 mg two times per day at week 4 based on the safety and changes in haemoglobin levels. Patients tolerating mitapivat well may be eligible to continue in two consecutive 24-week fixed dose periods.The primary objective of this study is to evaluate the safety of mitapivat, assessed through the occurrence of treatment-emergent adverse events. Secondary objectives include assessing the effects of mitapivat on haemoglobin levels, haemolysis, erythropoiesis, patient-reported outcome measures and spleen size.SATISFY aims to assess the safety and efficacy of mitapivat in adult patients with red blood cell membranopathies and CDA II, with the aim of establishing proof-of-concept in patients living with these rare conditions. ETHICS AND DISSEMINATION NCT05935202/CTIS:2023-503271-24-01. Findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER Clinicaltrials.gov, NCT05935202. CTIS:2023-503271-24-01. Registered 07-July-2023. Protocol number: 2.1. https://clinicaltrials.gov/study/NCT05935202.
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Affiliation(s)
- Andreas Glenthøj
- Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Eduard J van Beers
- Benign Hematology Center, Van Creveldkliniek, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Richard van Wijk
- Central Diagnostic Laboratory - Research, Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Urecht, Netherlands
| | - Minke A E Rab
- Central Diagnostic Laboratory - Research, Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Urecht, Netherlands
| | - Evelyn Groot
- Benign Hematology Center, Van Creveldkliniek, University Medical Centre Utrecht, Utrecht, Netherlands
| | - Niels Vejlstrup
- Department of Cardiology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Nina Toft
- Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Selma Kofoed Bendtsen
- Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jesper Petersen
- Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens Helby
- Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Fatiha Chermat
- EuroBloodNet Association, Université Paris Cité Faculté de Santé, Paris, France
| | - Pierre Fenaux
- EuroBloodNet Association, Université Paris Cité Faculté de Santé, Paris, France
| | - Kevin H M Kuo
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, Ontario, Canada
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48
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Zeng H, Zeng D, Yin X, Zhang W, Wu M, Chen Z. Research progress on high-concentration oxygen therapy after cerebral hemorrhage. Front Neurol 2024; 15:1410525. [PMID: 39139771 PMCID: PMC11320605 DOI: 10.3389/fneur.2024.1410525] [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: 04/01/2024] [Accepted: 07/18/2024] [Indexed: 08/15/2024] Open
Abstract
Recently, the role of high-concentration oxygen therapy in cerebral hemorrhage has been extensively discussed. This review describes the research progress in high-concentration oxygen therapy after cerebral hemorrhage. High-concentration oxygen therapy can be classified into two treatment methods: hyperbaric and normobaric high-concentration oxygen therapy. Several studies have reported that high-concentration oxygen therapy uses the pathological mechanisms of secondary ischemia and hypoxia after cerebral hemorrhage as an entry point to improve cerebral oxygenation, metabolic rate, cerebral edema, intracranial pressure, and oxidative stress. We also elucidate the mechanisms by which molecules such as Hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor, and erythropoietin (EPO) may play a role in oxygen therapy. Although people are concerned about the toxicity of hyperoxia, combined with relevant literature, the evidence discussed in this article suggests that as long as the duration, concentration, pressure, and treatment interval of patients with cerebral hemorrhage are properly understood and oxygen is administered within the treatment window, it can be effective to avoid hyperoxic oxygen toxicity. Combined with the latest research, we believe that high-concentration oxygen therapy plays an important positive role in injuries and outcomes after cerebral hemorrhage, and we recommend expanding the use of normal-pressure high-concentration oxygen therapy for cerebral hemorrhage.
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Affiliation(s)
- He Zeng
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Dakai Zeng
- Department of Anorectal Surgery, Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Xiaoping Yin
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Wumiao Zhang
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Moxin Wu
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
| | - Zhiying Chen
- Department of Neurology, Clinical Medical School of Jiujiang University, Jiujiang, Jiangxi, China
- Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, China
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Grander M, Haschka D, Indelicato E, Kremser C, Amprosi M, Nachbauer W, Henninger B, Stefani A, Högl B, Fischer C, Seifert M, Kiechl S, Weiss G, Boesch S. Genetic Determined Iron Starvation Signature in Friedreich's Ataxia. Mov Disord 2024; 39:1088-1098. [PMID: 38686449 DOI: 10.1002/mds.29819] [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: 12/28/2023] [Revised: 04/02/2024] [Accepted: 04/09/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. OBJECTIVES The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. METHODS In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). RESULTS We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. CONCLUSIONS We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Manuel Grander
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - David Haschka
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Kremser
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Matthias Amprosi
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Wolfgang Nachbauer
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Benjamin Henninger
- Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Ambra Stefani
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Birgit Högl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christine Fischer
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Seifert
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Kiechl
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- VASCage, Centre on Clinical Stroke Research, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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Guerra A, Hamilton N, Rivera A, Demsko P, Guo S, Rivella S. Combination of a TGF-β ligand trap (RAP-GRL) and TMPRSS6-ASO is superior for correcting β-thalassemia. Am J Hematol 2024; 99:1300-1312. [PMID: 38659383 PMCID: PMC11166515 DOI: 10.1002/ajh.27332] [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: 12/11/2023] [Revised: 03/11/2024] [Accepted: 03/22/2024] [Indexed: 04/26/2024]
Abstract
A recently approved drug that induces erythroid cell maturation (luspatercept) has been shown to improve anemia and reduce the need for blood transfusion in non-transfusion-dependent as well as transfusion-dependent β-thalassemia (BT) patients. Although these results were predominantly positive, not all the patients showed the expected increase in hemoglobin (Hb) levels or transfusion burden reduction. Additional studies indicated that administration of luspatercept in transfusion-dependent BT was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content. Altogether, these studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management. As luspatercept does not appear to directly affect iron metabolism, we hypothesized that TMPRSS6-ASO could improve iron parameters and iron overload when co-administered with luspatercept. We used an agent analogous to murine luspatercept (RAP-GRL) and another novel therapeutic, IONIS TMPRSS6-LRx (TMPRSS6-ASO), a hepcidin inducer, to treat non-transfusion-dependent BT-intermedia mice. Our study shows that RAP-GRL alone improved red blood cell (RBC) production, with no or limited effect on splenomegaly and iron parameters. In contrast, TMPRSS6-ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre-clinical support for combining TMPRSS6-ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients.
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Affiliation(s)
- Amaliris Guerra
- Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
| | - Nolan Hamilton
- Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
| | - Ariel Rivera
- Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
| | - Perry Demsko
- Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
- University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Cell and Molecular Biology affinity group (CAMB), University of Pennsylvania, Philadelphia, PA, USA
| | - Shuling Guo
- Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA
| | - Stefano Rivella
- Department of Pediatrics, Division of Hematology, The Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA, USA
- University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Cell and Molecular Biology affinity group (CAMB), University of Pennsylvania, Philadelphia, PA, USA
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics-CHOP
- Penn Center for Musculoskeletal Disorders, CHOP, Philadelphia, PA, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA
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