ArticleProceedings of the National Academy of Sciences of the United States of America2013
Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 97 citations in OpenAlex.
- Unveiling melatonin's multifaceted actions against ferroptotic neurotoxicity in ischemic stroke.Toxicology reports · 2026Review
- Vitamin B6 deficiency anemia resembles iron-deficiency anemia but does not activate intestinal HIF2⍺.Experimental hematology · 2026Article
- Uric Acid Induces Hepatocytes Ferroptosis Through HIF-2α/DMT1-Mediated Iron Overload.International journal of molecular sciences · 2026Article
- Intestine-Specific Ferroportin Ablation Rescues from Systemic Iron Overload in Mice.Nutrients · 2026Article
- Hemolysis-induced hepatic ferroptosis following xenotransfusion of genetically modified pig red blood cells.Scientific reports · 2025Article
- Predictive value of hepcidin and HIF1α protein levels for iron deposition in β-thalassemia.European journal of pediatrics · 2025Article
- The Roles of DMT1 in Inflammatory and Degenerative Diseases.Molecular neurobiology · 2025Review
- The relationship between ghrelin and iron metabolism in beta thalassaemia major patients.Archives of medical science : AMS · 2025Article
- Iron-Loading Anemias.Advances in experimental medicine and biology · 2025Review
- Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke.CNS neuroscience & therapeutics · 2024Review
- Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Mechanisms controlling cellular and systemic iron homeostasis.Nature reviews. Molecular cell biology · 2024Review
- Copper metabolism in osteoarthritis and its relation to oxidative stress and ferroptosis in chondrocytes.Frontiers in molecular biosciences · 2024Review
- High-Altitude Hypoxia Induces Excessive Erythrocytosis in Mice via Upregulation of the IntestinalBiomedicines · 2023Article
- Novel potential therapeutics to modify iron metabolism and red cell synthesis in diseases associated with defective erythropoiesis.Haematologica · 2023Review
- Article
- Ironing out β-thalassemia during pregnancy.Blood · 2023Article
- Article
- TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis.Advances in therapy · 2023Review
- (De)ironing out sickle cell disease.Blood · 2023Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including β-thalassemia major, which is characterized by a defective β-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In β-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in β-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of β-thalassemia and are essential for excess iron accumulation in mouse models of β-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in β-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.
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