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Mechanisms controlling cellular and systemic iron homeostasis

Nature Reviews Molecular Cell Biology volume 25, pages 133–155 (2024)Cite this article

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Abstract

In mammals, hundreds of proteins use iron in a multitude of cellular functions, including vital processes such as mitochondrial respiration, gene regulation and DNA synthesis or repair. Highly orchestrated regulatory systems control cellular and systemic iron fluxes ensuring sufficient iron delivery to target proteins is maintained, while limiting its potentially deleterious effects in iron-mediated oxidative cell damage and ferroptosis. In this Review, we discuss how cells acquire, traffick and export iron and how stored iron is mobilized for iron–sulfur cluster and haem biogenesis. Furthermore, we describe how these cellular processes are fine-tuned by the combination of various sensory and regulatory systems, such as the iron-regulatory protein (IRP)–iron-responsive element (IRE) network, the nuclear receptor co-activator 4 (NCOA4)-mediated ferritinophagy pathway, the prolyl hydroxylase domain (PHD)–hypoxia-inducible factor (HIF) axis or the nuclear factor erythroid 2-related factor 2 (NRF2) regulatory hub. We further describe how these pathways interact with systemic iron homeostasis control through the hepcidin–ferroportin axis to ensure appropriate iron fluxes. This knowledge is key for the identification of novel therapeutic opportunities to prevent diseases of cellular and/or systemic iron mismanagement.

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Fig. 1: Systemic and cellular iron metabolism.
Fig. 2: Cellular iron uptake pathways.
Fig. 3: Iron trafficking inside the cell.
Fig. 4: Iron export pathways.
Fig. 5: Key regulatory pathways of iron metabolism in the cell.
Fig. 6: Hepcidin control of cellular iron efflux through ferroportin.
Fig. 7: Interplay between cellular and systemic iron control.

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References

  1. Muchowska, K. B., Varma, S. J. & Moran, J. Synthesis and breakdown of universal metabolic precursors promoted by iron. Nature 569, 104–107 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Andreini, C., Putignano, V., Rosato, A. & Banci, L. The human iron-proteome. Metallomics 10, 1223–1231 (2018).

    Article  CAS  PubMed  Google Scholar 

  3. Jiang, H. et al. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors. J. Exp. Med. https://doi.org/10.1084/jem.20210739 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Antoszczak, M. et al. Iron-sensitive prodrugs that trigger active ferroptosis in drug-tolerant pancreatic cancer cells. J. Am. Chem. Soc. 144, 11536–11545 (2022).

    Article  CAS  PubMed  Google Scholar 

  5. Cheng, Y., Zak, O., Aisen, P., Harrison, S. C. & Walz, T. Structure of the human transferrin receptor–transferrin complex. Cell 116, 565–576 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Yu, Y. et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood 136, 726–739 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bartnikas, T. B. Known and potential roles of transferrin in iron biology. Biometals 25, 677–686 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Parrow, N. L. et al. Lobe specificity of iron binding to transferrin modulates murine erythropoiesis and iron homeostasis. Blood 134, 1373–1384 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Levy, J. E., Jin, O., Fujiwara, Y., Kuo, F. & Andrews, N. C. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat. Genet. 21, 396–399 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, S. et al. Transferrin receptor 1-mediated iron uptake plays an essential role in hematopoiesis. Haematologica 105, 2071–2082 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu, W. et al. Lethal cardiomyopathy in mice lacking transferrin receptor in the heart. Cell Rep. 13, 533–545 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Matak, P. et al. Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice. Proc. Natl Acad. Sci. USA 113, 3428–3435 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Barrientos, T. et al. Metabolic catastrophe in mice lacking transferrin receptor in muscle. EBioMedicine 2, 1705–1717 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jabara, H. H. et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat. Genet. 48, 74–78 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Wang, Z. et al. Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production. Immunity 49, 80–92.e7 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Das, B. K. et al. Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton. eLife https://doi.org/10.7554/eLife.73539 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Li, J. et al. Transferrin receptor 1 regulates thermogenic capacity and cell fate in brown/beige adipocytes. Adv. Sci. 7, 1903366 (2020).

    Article  CAS  Google Scholar 

  18. Zhang, Z. et al. Adipocyte iron levels impinge on a fat–gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity. Cell Metab. 33, 1624–1639.e9 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fillebeen, C. et al. Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load. Blood 133, 344–355 (2019).

    Article  CAS  PubMed  Google Scholar 

  20. Fisher, A. L. et al. Functional role of endothelial transferrin receptor 1 in iron sensing and homeostasis. Am. J. Hematol. 97, 1548–1559 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Khalil, S. et al. A specialized pathway for erythroid iron delivery through lysosomal trafficking of transferrin receptor 2. Blood Adv. 1, 1181–1194 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pantopoulos, K. Inherited disorders of iron overload. Front. Nutr. 5, 103 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nai, A. et al. The second transferrin receptor regulates red blood cell production in mice. Blood 125, 1170–1179 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Montemiglio, L. C. et al. Cryo-EM structure of the human ferritin–transferrin receptor 1 complex. Nat. Commun. 10, 1121 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Radoshitzky, S. R. et al. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature 446, 92–96 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gruszczyk, J. et al. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science 359, 48–55 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Coulon, S. et al. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia. Nat. Med. 17, 1456–1465 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Senyilmaz, D. et al. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature 525, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jian, J., Yang, Q. & Huang, X. Src regulates Tyr20 phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival. J. Biol. Chem. 286, 35708–35715 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schmidt, P. J., Toran, P. T., Giannetti, A. M., Bjorkman, P. J. & Andrews, N. C. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 7, 205–214 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chen, A. C., Donovan, A., Ned-Sykes, R. & Andrews, N. C. Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis. Proc. Natl Acad. Sci. USA 112, 11714–11719 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ned, R. M., Swat, W. & Andrews, N. C. Transferrin receptor 1 is differentially required in lymphocyte development. Blood 102, 3711–3718 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Truman-Rosentsvit, M. et al. Ferritin is secreted via 2 distinct nonclassical vesicular pathways. Blood 131, 342–352 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, J. Y. et al. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev. Cell 16, 35–46 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, T. T. et al. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J. Exp. Med. 202, 955–965 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Han, J. et al. Iron uptake mediated by binding of H-ferritin to the TIM-2 receptor in mouse cells. PLoS ONE 6, e23800 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, L. et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc. Natl Acad. Sci. USA 107, 3505–3510 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bao, G. et al. Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex. Nat. Chem. Biol. 6, 602–609 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Devireddy, L. R., Gazin, C., Zhu, X. & Green, M. R. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123, 1293–1305 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Mori, K. et al. Endocytic delivery of lipocalin–siderophore–iron complex rescues the kidney from ischemia–reperfusion injury. J. Clin. Invest. 115, 610–621 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chi, Y. et al. Cancer cells deploy lipocalin-2 to collect limiting iron in leptomeningeal metastasis. Science 369, 276–282 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Silva, A. M. N. & Rangel, M. The (bio)chemistry of non-transferrin-bound iron. Molecules https://doi.org/10.3390/molecules27061784 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Vali, S. W. & Lindahl, P. A. Might nontransferrin-bound iron in blood plasma and sera be a nonproteinaceous high-molecular-mass Fe(III) aggregate? J. Biol. Chem. 298, 102667 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jenkitkasemwong, S. et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22, 138–150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tripathi, A. K. et al. Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. Free Radic. Biol. Med. 84, 322–330 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang, V. et al. A mouse model characterizes the roles of ZIP8 in systemic iron recycling and lung inflammation and infection. Blood Adv. https://doi.org/10.1182/bloodadvances.2022007867 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ji, C. & Kosman, D. J. Molecular mechanisms of non-transferrin-bound and transferring-bound iron uptake in primary hippocampal neurons. J. Neurochem. 133, 668–683 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. van Raaij, S. E. G., Srai, S. K. S., Swinkels, D. W. & van Swelm, R. P. L. Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells. Biometals 32, 211–226 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kumfu, S., Chattipakorn, S. C. & Chattipakorn, N. Iron overload cardiomyopathy: using the latest evidence to inform future applications. Exp. Biol. Med. 247, 574–583 (2022).

    Article  CAS  Google Scholar 

  50. Hasna, J., Abi Nahed, R., Sergent, F., Alfaidy, N. & Bouron, A. The deletion of TRPC6 channels perturbs iron and zinc homeostasis and pregnancy outcome in mice. Cell Physiol. Biochem. 52, 455–467 (2019).

    Article  CAS  PubMed  Google Scholar 

  51. Gunshin, H. et al. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115, 1258–1266 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shawki, A. et al. Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G635–G647 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Gunshin, H. et al. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 106, 2879–2883 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shawki, A. et al. Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G423–G430 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Muller, S. et al. CD44 regulates epigenetic plasticity by mediating iron endocytosis. Nat. Chem. 12, 929–938 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. White, C. et al. HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab. 17, 261–270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rajagopal, A. et al. Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins. Nature 453, 1127–1131 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Unlu, G. et al. Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability. Mol. Cell 82, 2832–2843.e7 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang, Z. et al. CYB561A3 is the key lysosomal iron reductase required for Burkitt B-cell growth and survival. Blood 138, 2216–2230 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Meng, F. et al. Lysosomal iron recycling in mouse macrophages is dependent upon both LcytB and Steap3 reductases. Blood Adv. 6, 1692–1707 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhao, N., Gao, J., Enns, C. A. & Knutson, M. D. ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J. Biol. Chem. 285, 32141–32150 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dong, X. P. et al. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455, 992–996 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Grishchuk, Y. et al. Impaired myelination and reduced brain ferric iron in the mouse model of mucolipidosis IV. Dis. Model. Mech. 8, 1591–1601 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Yambire, K. F. et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. eLife https://doi.org/10.7554/eLife.51031 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Miles, A. L., Burr, S. P., Grice, G. L. & Nathan, J. A. The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels. eLife https://doi.org/10.7554/eLife.22693 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Sobh, A. et al. Genetic screens reveal CCDC115 as a modulator of erythroid iron and heme trafficking. Am. J. Hematol. 95, 1085–1098 (2020).

    Article  CAS  PubMed  Google Scholar 

  67. Weber, R. A. et al. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol. Cell 77, 645–655.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhu, X., Zhang, H. & Mendell, J. T. Ribosome recycling by ABCE1 links lysosomal function and iron homeostasis to 3′ UTR-directed regulation and nonsense-mediated decay. Cell Rep. 32, 107895 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Aronova, M. A. et al. Use of dual-electron probes reveals the role of ferritin as an iron depot in ex vivo erythropoiesis. iScience 24, 102901 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hamdi, A. et al. Erythroid cell mitochondria receive endosomal iron by a “kiss-and-run” mechanism. Biochim. Biophys. Acta 1863, 2859–2867 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Das, A., Nag, S., Mason, A. B. & Barroso, M. M. Endosome–mitochondria interactions are modulated by iron release from transferrin. J. Cell Biol. 214, 831–845 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wolff, N. A. et al. A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Sci. Rep. 8, 211 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Shaw, G. C. et al. Mitoferrin is essential for erythroid iron assimilation. Nature 440, 96–100 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Paradkar, P. N., Zumbrennen, K. B., Paw, B. H., Ward, D. M. & Kaplan, J. Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol. Cell Biol. 29, 1007–1016 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Christenson, E. T., Gallegos, A. S. & Banerjee, A. In vitro reconstitution, functional dissection, and mutational analysis of metal ion transport by mitoferrin-1. J. Biol. Chem. 293, 3819–3828 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Seguin, A. et al. The mitochondrial metal transporters mitoferrin1 and mitoferrin2 are required for liver regeneration and cell proliferation in mice. J. Biol. Chem. 295, 11002–11020 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Troadec, M. B. et al. Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood 117, 5494–5502 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Amigo, J. D. et al. Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis. Mol. Cell Biol. 31, 1344–1356 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Huang, J. et al. Dynamic control of enhancer repertoires drives lineage and stage-specific transcription during hematopoiesis. Dev. Cell 36, 9–23 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Chen, W. et al. Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. Proc. Natl Acad. Sci. USA 106, 16263–16268 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yamamoto, M. et al. Abcb10 role in heme biosynthesis in vivo: Abcb10 knockout in mice causes anemia with protoporphyrin IX and iron accumulation. Mol. Cell Biol. 34, 1077–1084 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Chen, W., Dailey, H. A. & Paw, B. H. Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood 116, 628–630 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Medlock, A. E. et al. Identification of the mitochondrial heme metabolism complex. PLoS ONE 10, e0135896 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Baldauf, L. et al. Mitoferrin-1 is required for brain energy metabolism and hippocampus-dependent memory. Neurosci. Lett. 713, 134521 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kumfu, S., Chattipakorn, S., Fucharoen, S. & Chattipakorn, N. Mitochondrial calcium uniporter blocker prevents cardiac mitochondrial dysfunction induced by iron overload in thalassemic mice. Biometals 25, 1167–1175 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Froschauer, E. M. et al. The mitochondrial carrier Rim2 co-imports pyrimidine nucleotides and iron. Biochem. J. 455, 57–65 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Knight, S. A. B. et al. Splitting the functions of Rim2, a mitochondrial iron/pyrimidine carrier. Mitochondrion 47, 256–265 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Monteith, A. J. et al. Mitochondrial calcium uniporter affects neutrophil bactericidal activity during Staphylococcus aureus infection. Infect. Immun. 90, e0055121 (2022).

    Article  PubMed  Google Scholar 

  89. Sweeny, E. A. et al. Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. J. Biol. Chem. 293, 14557–14568 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Galmozzi, A. et al. PGRMC2 is an intracellular haem chaperone critical for adipocyte function. Nature 576, 138–142 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sun, F. et al. HRG-9 homologues regulate haem trafficking from haem-enriched compartments. Nature 610, 768–774 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ponka, P., Sheftel, A. D., English, A. M., Scott Bohle, D. & Garcia-Santos, D. Do mammalian cells really need to export and import heme. Trends Biochem. Sci. 42, 395–406 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Liu, G. et al. Heme biosynthesis depends on previously unrecognized acquisition of iron-sulfur cofactors in human amino-levulinic acid dehydratase. Nat. Commun. 11, 6310 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wingert, R. A. et al. Deficiency of glutaredoxin 5 reveals Fe–S clusters are required for vertebrate haem synthesis. Nature 436, 1035–1039 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Philpott, C. C., Patel, S. J. & Protchenko, O. Management versus miscues in the cytosolic labile iron pool: the varied functions of iron chaperones. Biochim. Biophys. Acta Mol. Cell Res. 1867, 118830 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Patel, S. J. et al. A PCBP1–BolA2 chaperone complex delivers iron for cytosolic [2Fe–2S] cluster assembly. Nat. Chem. Biol. 15, 872–881 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bae, D. H. et al. Acireductone dioxygenase 1 (ADI1) is regulated by cellular iron by a mechanism involving the iron chaperone, PCBP1, with PCBP2 acting as a potential co-chaperone. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165844 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Yanatori, I., Yasui, Y., Tabuchi, M. & Kishi, F. Chaperone protein involved in transmembrane transport of iron. Biochem. J. 462, 25–37 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Yanatori, I., Richardson, D. R., Toyokuni, S. & Kishi, F. The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. J. Biol. Chem. 292, 13205–13229 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yanatori, I., Richardson, D. R., Imada, K. & Kishi, F. Iron export through the transporter ferroportin 1 is modulated by the iron chaperone PCBP2. J. Biol. Chem. 291, 17303–17318 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ryu, M. S., Zhang, D., Protchenko, O., Shakoury-Elizeh, M. & Philpott, C. C. PCBP1 and NCOA4 regulate erythroid iron storage and heme biosynthesis. J. Clin. Invest. 127, 1786–1797 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Patel, S. J. et al. The iron chaperone and nucleic acid-binding activities of poly(rC)-binding protein 1 are separable and independently essential. Proc. Natl Acad. Sci. USA 118, e2104666118 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Protchenko, O. et al. Iron chaperone poly rC binding protein 1 protects mouse liver from lipid peroxidation and steatosis. Hepatology 73, 1176–1193 (2021).

    Article  CAS  PubMed  Google Scholar 

  104. Sen, S. et al. Intracellular pathogen Leishmania intervenes in iron loading into ferritin by cleaving chaperones in host macrophages as an iron acquisition strategy. J. Biol. Chem. 298, 102646 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Koorts, A. M. & Viljoen, M. Ferritin and ferritin isoforms I: structure–function relationships, synthesis, degradation and secretion. Arch. Physiol. Biochem. 113, 30–54 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Li, W. et al. Systemic and cerebral iron homeostasis in ferritin knock-out mice. PLoS ONE 10, e0117435 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Ferreira, C. et al. Early embryonic lethality of H ferritin gene deletion in mice. J. Biol. Chem. 275, 3021–3024 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Blankenhaus, B. et al. Ferritin regulates organismal energy balance and thermogenesis. Mol. Metab. 24, 64–79 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ikeda, Y. et al. Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice. Diabetologia 63, 1588–1602 (2020).

    Article  CAS  PubMed  Google Scholar 

  110. Zarjou, A. et al. Ferritin light chain confers protection against sepsis-induced inflammation and organ injury. Front. Immunol. 10, 131 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Moreira, A. C. et al. H-Ferritin produced by myeloid cells is released to the circulation and plays a major role in liver iron distribution during infection. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23010269 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Reddy, V. P. et al. Ferritin H deficiency in myeloid compartments dysregulates host energy metabolism and increases susceptibility to Mycobacterium tuberculosis infection. Front. Immunol. 9, 860 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Patino, E. et al. Iron therapy mitigates chronic kidney disease progression by regulating intracellular iron status of kidney macrophages. JCI Insight https://doi.org/10.1172/jci.insight.159235 (2023).

  114. Haschka, D. et al. Ferritin H deficiency deteriorates cellular iron handling and worsens Salmonella typhimurium infection by triggering hyperinflammation. JCI Insight https://doi.org/10.1172/jci.insight.141760 (2021).

  115. Vanoaica, L. et al. Conditional deletion of ferritin H in mice reduces B and T lymphocyte populations. PLoS ONE 9, e89270 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Wan, R. et al. Impaired postnatal myelination in a conditional knockout mouse for the ferritin heavy chain in oligodendroglial cells. J. Neurosci. 40, 7609–7624 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cheli, V. T. et al. H-Ferritin expression in astrocytes is necessary for proper oligodendrocyte development and myelination. Glia 69, 2981–2998 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schweizer, C., Fraering, P. C. & Kuhn, L. C. Ferritin H gene deletion in the choroid plexus and forebrain results in hydrocephalus. Neurochem. Int. 71, 17–21 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Weis, S. et al. Metabolic adaptation establishes disease tolerance to sepsis. Cell 169, 1263–1275.e14 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zarjou, A. et al. Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury. J. Clin. Invest. 123, 4423–4434 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Fang, X. et al. Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis. Circ. Res. 127, 486–501 (2020).

    Article  CAS  PubMed  Google Scholar 

  122. Darshan, D., Vanoaica, L., Richman, L., Beermann, F. & Kuhn, L. C. Conditional deletion of ferritin H in mice induces loss of iron storage and liver damage. Hepatology 50, 852–860 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Thomas B. et al.Characterization of mitochondrial ferritin-deficient mice. Am. J. Hematol. 85, 958–960 (2010).

    Article  Google Scholar 

  124. Maccarinelli, F. et al. Mice lacking mitochondrial ferritin are more sensitive to doxorubicin-mediated cardiotoxicity. J. Mol. Med. 92, 859–869 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Shi, Z. H. et al. Neuroprotective mechanism of mitochondrial ferritin on 6-hydroxydopamine-induced dopaminergic cell damage: implication for neuroprotection in Parkinson’s disease. Antioxid. Redox Signal. 13, 783–796 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang, P. et al. Mitochondrial ferritin deletion exacerbates beta-amyloid-induced neurotoxicity in mice. Oxid. Med. Cell Longev. 2017, 1020357 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Wang, P. et al. Mitochondrial ferritin attenuates cerebral ischaemia/reperfusion injury by inhibiting ferroptosis. Cell Death Dis. 12, 447 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wang, P. et al. Mitochondrial ferritin alleviates apoptosis by enhancing mitochondrial bioenergetics and stimulating glucose metabolism in cerebral ischemia reperfusion. Redox Biol. 57, 102475 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Vanoaica, L., Darshan, D., Richman, L., Schumann, K. & Kuhn, L. C. Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab. 12, 273–282 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Jia, J. et al. Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis. Nat. Commun. 13, 6804 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yu, B. et al. Interactions of ferritin with scavenger receptor class A members. J. Biol. Chem. 295, 15727–15741 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cheung, P. et al. Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation. Nat. Immunol. 22, 711–722 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Muckenthaler, M. U., Rivella, S., Hentze, M. W. & Galy, B. A red carpet for iron metabolism. Cell 168, 344–361 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wu, Q. et al. Renal control of life-threatening malarial anemia. Cell Rep. 42, 112057 (2023).

    Article  CAS  PubMed  Google Scholar 

  135. Taniguchi, R. et al. Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat. Commun. 6, 8545 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Pan, Y. et al. Structural basis of ion transport and inhibition in ferroportin. Nat. Commun. 11, 5686 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Billesbolle, C. B. et al. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature 586, 807–811 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Deshpande, C. N. et al. Calcium is an essential cofactor for metal efflux by the ferroportin transporter family. Nat. Commun. 9, 3075 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Shen, J., Wilbon, A. S., Zhou, M. & Yaping, P. Mechanism of Ca2+ transport by ferroportin. eLife https://doi.org/10.7554/eLife.82947 (2023).

  140. Helman, S. L. et al. The placental ferroxidase zyklopen is not essential for iron transport to the fetus in mice. J. Nutr. 151, 2541–2550 (2021).

    Article  CAS  PubMed  Google Scholar 

  141. Zhang, D. L. et al. Erythrocytic ferroportin reduces intracellular iron accumulation, hemolysis, and malaria risk. Science 359, 1520–1523 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Muriuki, J. M. et al. The ferroportin Q248H mutation protects from anemia, but not malaria or bacteremia. Sci. Adv. 5, eaaw0109 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang, D. L., Ghosh, M. C., Ollivierre, H., Li, Y. & Rouault, T. A. Ferroportin deficiency in erythroid cells causes serum iron deficiency and promotes hemolysis due to oxidative stress. Blood 132, 2078–2087 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lakhal-Littleton, S. et al. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. eLife https://doi.org/10.7554/eLife.19804 (2016).

  145. Fang, X., Wang, H., An, P., Min, J. & Wang, F. Cardiomyocyte-specific deletion of ferroportin using MCK-Cre has no apparent effect on cardiac iron homeostasis. Int. J. Cardiol. 201, 90–92 (2015).

    Article  PubMed  Google Scholar 

  146. Corna, G. et al. The repair of skeletal muscle requires iron recycling through macrophage ferroportin. J. Immunol. 197, 1914–1925 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Sangkhae, V. et al. Effects of maternal iron status on placental and fetal iron homeostasis. J. Clin. Invest. 130, 625–640 (2020).

    Article  CAS  PubMed  Google Scholar 

  148. Cao, C. & Fleming, M. D. Loss of the placental iron exporter ferroportin 1 causes embryonic demise in late-gestation mouse pregnancy. Development https://doi.org/10.1242/dev.201160 (2022).

  149. Mohammad, G., Matakidou, A., Robbins, P. A. & Lakhal-Littleton, S. The kidney hepcidin/ferroportin axis controls iron reabsorption and determines the magnitude of kidney and systemic iron overload. Kidney Int. 100, 559–569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wang, X. et al. Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury. Am. J. Physiol. Ren. Physiol. 315, F1042–F1057 (2018).

    Article  CAS  Google Scholar 

  151. Bessman, N. J. et al. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science 368, 186–189 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Gao, H. et al. Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metab. 34, 1201–1213.e5 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ito, F., Kato, K., Yanatori, I., Murohara, T. & Toyokuni, S. Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin. Redox Biol. 47, 102174 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kimura, T. et al. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J. 36, 42–60 (2017).

    Article  CAS  PubMed  Google Scholar 

  155. Brown, C. W. et al. Prominin2 drives ferroptosis resistance by stimulating iron export. Dev. Cell 51, 575–586.e4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Yanatori, I., Richardson, D. R., Dhekne, H. S., Toyokuni, S. & Kishi, F. CD63 is regulated by iron via the IRE–IRP system and is important for ferritin secretion by extracellular vesicles. Blood 138, 1490–1503 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sinclair, J. & Hamza, I. Lessons from bloodless worms: heme homeostasis in C. elegans. Biometals 28, 481–489 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jonker, J. W. et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc. Natl Acad. Sci. USA 99, 15649–15654 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Korolnek, T., Zhang, J., Beardsley, S., Scheffer, G. L. & Hamza, I. Control of metazoan heme homeostasis by a conserved multidrug resistance protein. Cell Metab. 19, 1008–1019 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Muckenthaler, M., Gray, N. K. & Hentze, M. W. IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F. Mol. Cell 2, 383–388 (1998).

    Article  CAS  PubMed  Google Scholar 

  161. Yoshinaga, M. et al. Regnase-1 maintains iron homeostasis via the degradation of transferrin receptor 1 and prolyl-hydroxylase-domain-containing protein 3 mRNAs. Cell Rep. 19, 1614–1630 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Corral, V. M., Schultz, E. R., Eisenstein, R. S. & Connell, G. J. Roquin is a major mediator of iron-regulated changes to transferrin receptor-1 mRNA stability. iScience 24, 102360 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Tybl, E. et al. Control of systemic iron homeostasis by the 3′ iron-responsive element of divalent metal transporter 1 in mice. Hemasphere 4, e459 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Qatato, M. et al. IRE-dependent regulation of intestinal Dmt1 prevails during chronic dietary iron deficiency but is dispensable in conditions of acute erythropoietic stress. Hemasphere 6, e693 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Luscieti, S. et al. The actin-binding protein profilin 2 is a novel regulator of iron homeostasis. Blood 130, 1934–1945 (2017).

    Article  CAS  PubMed  Google Scholar 

  166. Sanchez, M., Galy, B., Muckenthaler, M. U. & Hentze, M. W. Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency. Nat. Struct. Mol. Biol. 14, 420–426 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Dandekar, T. et al. Identification of a novel iron-responsive element in murine and human erythroid δ-aminolevulinic acid synthase mRNA. EMBO J. 10, 1903–1909 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Anderson, S. A. et al. The IRP1–HIF-2α axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 17, 282–290 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wilkinson, N. & Pantopoulos, K. IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation. Blood 122, 1658–1668 (2013).

    Article  CAS  PubMed  Google Scholar 

  170. Ghosh, M. C. et al. Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2α. Cell Metab. 17, 271–281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Shen, M., Goforth, J. B. & Eisenstein, R. S. Iron-dependent post transcriptional control of mitochondrial aconitase expression. Metallomics https://doi.org/10.1093/mtomcs/mfac099 (2023).

  172. Kim, H. Y., LaVaute, T., Iwai, K., Klausner, R. D. & Rouault, T. A. Identification of a conserved and functional iron-responsive element in the 5′-untranslated region of mammalian mitochondrial aconitase. J. Biol. Chem. 271, 24226–24230 (1996).

    Article  CAS  PubMed  Google Scholar 

  173. Sanchez, M. et al. Iron regulation and the cell cycle: identification of an iron-responsive element in the 3′-untranslated region of human cell division cycle 14A mRNA by a refined microarray-based screening strategy. J. Biol. Chem. 281, 22865–22874 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. Connell, G. J., Danial, J. S. & Haastruthers, C. X. Evaluation of the iron regulatory protein-1 interactome. Biometals 31, 139–146 (2018).

    Article  CAS  PubMed  Google Scholar 

  175. Corley, M. et al. Footprinting SHAPE-eCLIP reveals transcriptome-wide hydrogen bonds at RNA–protein interfaces. Mol. Cell 80, 903–914.e8 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hognon, C. et al. The iron maiden. Cytosolic aconitase/IRP1 conformational transition in the regulation of ferritin translation and iron hemostasis. Biomolecules https://doi.org/10.3390/biom11091329 (2021).

  177. Oskarsson, G. R. et al. Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis. Commun. Biol. 3, 189 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Wang, H. et al. FBXL5 regulates IRP2 stability in iron homeostasis via an oxygen-responsive [2Fe2S] cluster. Mol. Cell 78, 31–41.e5 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Salahudeen, A. A. et al. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326, 722–726 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Vashisht, A. A. et al. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326, 718–721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Thompson, J. W. et al. Structural and molecular characterization of iron-sensing hemerythrin-like domain within F-box and leucine-rich repeat protein 5 (FBXL5). J. Biol. Chem. 287, 7357–7365 (2012).

    Article  Google Scholar 

  182. Mayank, A. K. et al. An oxygen-dependent interaction between FBXL5 and the CIA-targeting complex regulates iron homeostasis. Mol. Cell 75, 382–393.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Terzi, E. M., Sviderskiy, V. O., Alvarez, S. W., Whiten, G. C. & Possemato, R. Iron–sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5. Sci. Adv. https://doi.org/10.1126/sciadv.abg4302 (2021).

  184. Muto, Y., Nishiyama, M., Nita, A., Moroishi, T. & Nakayama, K. I. Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells. Nat. Commun. 8, 16114 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Smith, S. R., Ghosh, M. C., Ollivierre-Wilson, H., Hang Tong, W. & Rouault, T. A. Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. Blood Cell Mol. Dis. 36, 283–287 (2006).

    Article  CAS  Google Scholar 

  186. Galy, B., Ferring-Appel, D., Kaden, S., Grone, H. J. & Hentze, M. W. Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab. 7, 79–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Galy, B. et al. Iron regulatory proteins control a mucosal block to intestinal iron absorption. Cell Rep. 3, 844–857 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Galy, B. et al. Iron regulatory proteins secure mitochondrial iron sufficiency and function. Cell Metab. 12, 194–201 (2010).

    Article  CAS  PubMed  Google Scholar 

  189. Nairz, M. et al. Iron regulatory proteins mediate host resistance to Salmonella infection. Cell Host Microbe 18, 254–261 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Frost, J. N. et al. Hepcidin-mediated hypoferremia disrupts immune responses to vaccination and infection. Med 2, 164–179.e12 (2021).

    Article  CAS  PubMed  Google Scholar 

  191. Bonadonna, M. et al. Iron regulatory protein (IRP)-mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow. Sci. Adv. 8, eabq4469 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Haddad, S. et al. Iron-regulatory proteins secure iron availability in cardiomyocytes to prevent heart failure. Eur. Heart J. 38, 362–372 (2017).

    CAS  PubMed  Google Scholar 

  193. Galy, B. et al. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood 106, 2580–2589 (2005).

    Article  CAS  PubMed  Google Scholar 

  194. Cooperman, S. S. et al. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood 106, 1084–1091 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Galy, B. et al. Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat. Genet. 38, 967–969; discussion 969–970 (2006).

    Article  CAS  PubMed  Google Scholar 

  196. LaVaute, T. et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat. Genet. 27, 209–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  197. Zumbrennen-Bullough, K. B. et al. Abnormal brain iron metabolism in Irp2 deficient mice is associated with mild neurological and behavioral impairments. PLoS ONE 9, e98072 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Cooper, M. S., Stark, Z., Lunke, S., Zhao, T. & Amor, D. J. IREB2-associated neurodegeneration. Brain 142, e40 (2019).

    Article  PubMed  Google Scholar 

  199. Costain, G. et al. Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome. Brain 142, 1195–1202 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Maio, N. et al. Disruption of cellular iron homeostasis by IREB2 missense variants causes severe neurodevelopmental delay, dystonia and seizures. Brain Commun. 4, fcac102 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Dowdle, W. E. et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat. Cell Biol. 16, 1069–1079 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. Ohshima, T., Yamamoto, H., Sakamaki, Y., Saito, C. & Mizushima, N. NCOA4 drives ferritin phase separation to facilitate macroferritinophagy and microferritinophagy. J. Cell Biol. https://doi.org/10.1083/jcb.202203102 (2022).

  204. Kuno, S., Fujita, H., Tanaka, Y. K., Ogra, Y. & Iwai, K. Iron-induced NCOA4 condensation regulates ferritin fate and iron homeostasis. EMBO Rep. 23, e54278 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Das, N. K. et al. Modulation of the HIF2α–NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis. Blood 139, 2547–2552 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Li, X. et al. NCOA4 is regulated by HIF and mediates mobilization of murine hepatic iron stores after blood loss. Blood 136, 2691–2702 (2020).

    PubMed  PubMed Central  Google Scholar 

  207. Wu, H., Liu, Q., Shan, X., Gao, W. & Chen, Q. ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy 19, 1–16 (2023).

    Article  CAS  Google Scholar 

  208. Nai, A. et al. NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice. Haematologica 106, 795–805 (2021).

    CAS  PubMed  Google Scholar 

  209. Santana-Codina, N. et al. NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron–sulfur cluster proteins. Cancer Discov. 12, 2180–2197 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Ravichandran, M. et al. Coordinated transcriptional and catabolic programs support iron-dependent adaptation to RAS–MAPK pathway inhibition in pancreatic cancer. Cancer Discov. 12, 2198–2219 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Ito, J. et al. Iron derived from autophagy-mediated ferritin degradation induces cardiomyocyte death and heart failure in mice. eLife https://doi.org/10.7554/eLife.62174 (2021).

  212. Fang, Y. et al. Inhibiting ferroptosis through disrupting the NCOA4–FTH1 interaction: a new mechanism of action. ACS Cent. Sci. 7, 980–989 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Li, Y. et al. Cell-specific metabolic reprogramming of tumors for bioactivatable ferroptosis therapy. ACS Nano 16, 3965–3984 (2022).

    Article  CAS  PubMed  Google Scholar 

  214. Ohta, K., Saka, N. & Nishio, M. Human parainfluenza virus type 2 V protein modulates iron homeostasis. J. Virol. https://doi.org/10.1128/JVI.01861-20 (2021).

  215. Yan, Q. et al. Iron robbery by intracellular pathogen via bacterial effector-induced ferritinophagy. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2026598118 (2021).

  216. Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).

    Article  CAS  PubMed  Google Scholar 

  217. Lim, P. J. et al. Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nat. Metab. 1, 519–531 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Anandhan, A. et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci. Adv. 9, eade9585 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Dodson, M., Castro-Portuguez, R. & Zhang, D. D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 23, 101107 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Silva-Gomes, S. et al. Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death. J. Hepatol. 60, 354–361 (2014).

    Article  CAS  PubMed  Google Scholar 

  221. Duarte, T. L. et al. Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis. Redox Biol. 11, 157–169 (2017).

    Article  CAS  PubMed  Google Scholar 

  222. Kragesteen, B. K. et al. The transcriptional and regulatory identity of erythropoietin producing cells. Nat. Med. 29, 1191–1200 (2023).

    Article  CAS  PubMed  Google Scholar 

  223. Gassmann, M. & Muckenthaler, M. U. Adaptation of iron requirement to hypoxic conditions at high altitude. J. Appl. Physiol. 119, 1432–1440 (2015).

    Article  CAS  PubMed  Google Scholar 

  224. Haase, V. H. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial. Int. 21, S110–S124 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Siegert, I. et al. Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1α upon LPS activation in the presence of ample oxygen. Cell Rep. 13, 2048–2055 (2015).

    Article  CAS  PubMed  Google Scholar 

  226. Mastrogiannaki, M. et al. Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica 97, 827–834 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Kautz, L. et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46, 678–684 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Arezes, J. et al. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood 132, 1473–1477 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Wang, C. Y. et al. Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from binding to the BMP type I receptor ALK3. Blood 135, 453–456 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Anderson, E. R. et al. Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia. Proc. Natl Acad. Sci. USA 110, E4922–E4930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Das, N. et al. Intestine-specific disruption of hypoxia-inducible factor (HIF)-2α improves anemia in sickle cell disease. J. Biol. Chem. 290, 23523–23527 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Jiang, L. et al. RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation. Blood 138, 689–705 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Traeger, L. et al. UBA6 and NDFIP1 regulate the degradation of ferroportin. Haematologica 107, 478–488 (2022).

    Article  CAS  PubMed  Google Scholar 

  234. Link, C., Knopf, J. D., Marques, O., Lemberg, M. K. & Muckenthaler, M. U. The role of cellular iron deficiency in controlling iron export. Biochim. Biophys. Acta Gen. Subj. 1865, 129829 (2021).

    Article  CAS  PubMed  Google Scholar 

  235. Aschemeyer, S. et al. Structure–function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood 131, 899–910 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Qiu, R. et al. Repression of the iron exporter ferroportin may contribute to hepatocyte iron overload in individuals with type 2 diabetes. Mol. Metab. 66, 101644 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Guida, C. et al. A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia. Blood 125, 2265–2275 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Sangokoya, C., Doss, J. F. & Chi, J. T. Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin. PLoS Genet. 9, e1003408 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Babu, K. R. & Muckenthaler, M. U. miR-20a regulates expression of the iron exporter ferroportin in lung cancer. J. Mol. Med. 94, 347–359 (2016).

    Article  CAS  PubMed  Google Scholar 

  240. Katsarou, A., Gkouvatsos, K., Fillebeen, C. & Pantopoulos, K. Tissue-specific regulation of ferroportin in wild-type and Hjv–/– mice following dietary iron manipulations. Hepatol. Commun. 5, 2139–2150 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Charlebois, E. et al. A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice. eLife https://doi.org/10.7554/eLife.81332 (2022).

  242. Wang, C. Y. et al. Ablation of hepatocyte Smad1, Smad5, and Smad8 causes severe tissue iron loading and liver fibrosis in mice. Hepatology 70, 1986–2002 (2019).

    Article  CAS  PubMed  Google Scholar 

  243. Colucci, S., Marques, O. & Altamura, S. 20 years of hepcidin: how far we have come. Semin. Hematol. 58, 132–144 (2021).

    Article  PubMed  Google Scholar 

  244. Muckenthaler, L. et al. Constitutional PIGA mutations cause a novel subtype of hemochromatosis in patients with neurologic dysfunction. Blood 139, 1418–1422 (2022).

    Article  CAS  PubMed  Google Scholar 

  245. Xiao, X. et al. Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia. Blood 141, 422–432 (2023).

    Article  CAS  PubMed  Google Scholar 

  246. Johnson, M. B. & Enns, C. A. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 104, 4287–4293 (2004).

    Article  CAS  PubMed  Google Scholar 

  247. Robb, A. & Wessling-Resnick, M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104, 4294–4299 (2004).

    Article  CAS  PubMed  Google Scholar 

  248. D’Alessio, F., Hentze, M. W. & Muckenthaler, M. U. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. J. Hepatol. 57, 1052–1060 (2012).

    Article  PubMed  Google Scholar 

  249. Corradini, E. et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)–SMAD signaling pathway in mice. Hepatology 54, 273–284 (2011).

    Article  CAS  PubMed  Google Scholar 

  250. Ramos, E. et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 53, 1333–1341 (2011).

    Article  CAS  PubMed  Google Scholar 

  251. Gao, J. et al. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 9, 217–227 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Pagani, A. et al. Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2. Haematologica 105, e493 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Xiao, X. et al. Endothelial bone morphogenetic protein 2 (Bmp2) knockout exacerbates hemochromatosis in homeostatic iron regulator (Hfe) knockout mice but not Bmp6 knockout mice. Hepatology 72, 642–655 (2020).

    Article  CAS  PubMed  Google Scholar 

  254. Silvestri, L. et al. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 8, 502–511 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Colucci, S. et al. The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. Blood 130, 2111–2120 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Buerkli, S. et al. The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption — a stable iron isotope study in Taiwanese women. Haematologica 106, 2897–2905 (2021).

    Article  CAS  PubMed  Google Scholar 

  257. Gill, D. et al. The effect of iron status on risk of coronary artery disease: a Mendelian randomization study — brief report. Arterioscler. Thromb. Vasc. Biol. 37, 1788–1792 (2017).

    Article  CAS  PubMed  Google Scholar 

  258. Barrows, I. R. et al. Race, interleukin-6, TMPRSS6 genotype, and cardiovascular disease in patients with chronic kidney disease. J. Am. Heart Assoc. 11, e025627 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Lakhal-Littleton, S. et al. Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice. Proc. Natl Acad. Sci. USA 116, 13122–13130 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Vinchi, F. et al. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood 127, 473–486 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Colucci, S. et al. Liver sinusoidal endothelial cells suppress bone morphogenetic protein 2 production in response to TGFβ pathway activation. Hepatology 74, 2186–2200 (2021).

    Article  CAS  PubMed  Google Scholar 

  262. Colucci, S., Mudder, K., Muckenthaler, M. U. & Altamura, S. Hfe is highly expressed in liver sinusoidal endothelial cells but is not needed to maintain systemic iron homeostasis in vivo. Hemasphere 6, e667 (2022).

    Article  CAS  PubMed  Google Scholar 

  263. Charlebois, E. et al. Liver sinusoidal endothelial cells induce BMP6 expression in response to non-transferrin-bound iron. Blood 141, 271–284 (2023).

    Article  CAS  PubMed  Google Scholar 

  264. Altamura, S. et al. Resistance of ferroportin to hepcidin binding causes exocrine pancreatic failure and fatal iron overload. Cell Metab. 20, 359–367 (2014).

    Article  CAS  PubMed  Google Scholar 

  265. Huang, F. W., Pinkus, J. L., Pinkus, G. S., Fleming, M. D. & Andrews, N. C. A mouse model of juvenile hemochromatosis. J. Clin. Invest. 115, 2187–2191 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Rausa, M. et al. Bmp6 expression in murine liver non parenchymal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload. PLoS ONE 10, e0122696 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Colucci, S. et al. Iron-dependent BMP6 regulation in liver sinusoidal endothelial cells is instructed by hepatocyte-derived secretory signals. Hemasphere 6, e773 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Li, Y. et al. Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism. Hepatol. Int. https://doi.org/10.1007/s12072-022-10452-2 (2022).

  269. Coffey, R. et al. Erythroid overproduction of erythroferrone causes iron overload and developmental abnormalities in mice. Blood 139, 439–451 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. McKie, A. T. et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 291, 1755–1759 (2001).

    Article  CAS  PubMed  Google Scholar 

  271. Fillebeen, C. et al. Mice are poor heme absorbers and do not require intestinal Hmox1 for dietary heme iron assimilation. Haematologica 100, e334–e337 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Gardenghi, S. et al. Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 109, 5027–5035 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Ma, X. et al. SMAD family member 3 (SMAD3) and SMAD4 repress HIF2α-dependent iron-regulatory genes. J. Biol. Chem. 294, 3974–3986 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Zhang, D. L., Hughes, R. M., Ollivierre-Wilson, H., Ghosh, M. C. & Rouault, T. A. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab. 9, 461–473 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Das, N. K. et al. Microbial metabolite signaling is required for systemic iron homeostasis. Cell Metab. 31, 115–130.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  276. Chen, M. et al. Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts. Blood 140, 1145–1155 (2022).

    Article  CAS  PubMed  Google Scholar 

  277. Volz, K. Conservation in the iron responsive element family. Genes https://doi.org/10.3390/genes12091365 (2021).

  278. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  280. Seiler, A. et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8, 237–248 (2008).

    Article  CAS  PubMed  Google Scholar 

  281. Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).

    Article  CAS  PubMed  Google Scholar 

  283. Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).

    Article  CAS  PubMed  Google Scholar 

  284. Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).

    Article  CAS  PubMed  Google Scholar 

  287. Soula, M. et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol. 16, 1351–1360 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Dixon, S. J. et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol. 10, 1604–1609 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Beharier, O. et al. PLA2G6 guards placental trophoblasts against ferroptotic injury. Proc. Natl Acad. Sci. USA 117, 27319–27328 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Sun, W. Y. et al. Phospholipase iPLA2β averts ferroptosis by eliminating a redox lipid death signal. Nat. Chem. Biol. 17, 465–476 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Chen, D. et al. iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat. Commun. 12, 3644 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Li, Y., Maher, P. & Schubert, D. A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19, 453–463 (1997).

    Article  CAS  PubMed  Google Scholar 

  293. Matsushita, M. et al. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212, 555–568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Zou, Y. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat. Chem. Biol. 16, 302–309 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Yan, B. et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell 81, 355–369.e10 (2021).

    Article  CAS  PubMed  Google Scholar 

  296. Samarin, J. et al. Low level of antioxidant capacity biomarkers but not target overexpression predicts vulnerability to ROS-inducing drugs. Redox Biol. 62, 102639 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Conrad, M. & Pratt, D. A. The chemical basis of ferroptosis. Nat. Chem. Biol. 15, 1137–1147 (2019).

    Article  CAS  PubMed  Google Scholar 

  298. Jakaria, M., Belaidi, A. A., Bush, A. I. & Ayton, S. Ferroptosis as a mechanism of neurodegeneration in Alzheimer’s disease. J. Neurochem. 159, 804–825 (2021).

    Article  CAS  PubMed  Google Scholar 

  299. Kenkhuis, B., Bush, A. I. & Ayton, S. How iron can drive neurodegeneration. Trends Neurosci. https://doi.org/10.1016/j.tins.2023.02.003 (2023).

  300. Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Hou, W. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12, 1425–1428 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Xia, H. et al. N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2. Cell Death Differ. https://doi.org/10.1038/s41418-023-01138-9 (2023).

  303. Zhang, T. et al. ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat. Cancer 3, 75–89 (2022).

    Article  CAS  PubMed  Google Scholar 

  304. Torti, S. V., Manz, D. H., Paul, B. T., Blanchette-Farra, N. & Torti, F. M. Iron and cancer. Annu. Rev. Nutr. 38, 97–125 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Mai, T. T. et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat. Chem. 9, 1025–1033 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Zhou, L. et al. Ferroptosis — a new dawn in the treatment of organ ischemia–reperfusion injury. Cells https://doi.org/10.3390/cells11223653 (2022).

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Acknowledgements

The authors thank S. Altamura (University of Heidelberg) for help with retrieving data on iron proteins and N. Gunkel (German Cancer Research Center (DKFZ)) for critical feedback on the manuscript. B.G. is the recipient of a grant from the Deutsche Forschungsgemeinschaft (DFG) (GA 2075/6-1). M.U.M. acknowledges funding from the DFG (FerrOs FOR5146, Priority Program SPP 2306, GRK2727), Federal Ministry of Education and Research (BMBF) (NephrESA project Nr 031L0191C), Dietmar Hopp-Stiftung and Deutscher Akademischer Austauschdienst (A New Passage to India). M.C. acknowledges funding from the DFG (CO 291/9-1, #461385412; and the Priority Program SPP 2306 (CO 291/9-1, #461385412; CO 291/10-1, #461507177)), BMBF (FERROPath 01EJ2205B), Else Kröner-Fresenius-Stiftung (Projects 2019_T12, 2020_EKTP19) and European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. GA 884754). The original figures were generated with the assistance of BioRender.

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Authors and Affiliations

  1. German Cancer Research Center (DKFZ), Division of Virus-associated Carcinogenesis (F170), Heidelberg, Germany

    Bruno Galy

  2. Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Neuherberg, Germany

    Marcus Conrad

  3. Department of Paediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany

    Martina Muckenthaler

  4. Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany

    Martina Muckenthaler

  5. German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Heidelberg, Germany

    Martina Muckenthaler

  6. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany

    Martina Muckenthaler

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The authors contributed equally to all aspects of the article.

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Glossary

Capsular cells

Stromal cells in the outermost layer of the renal cortex that provide a signalling environment crucial for normal patterning of the developing kidney.

Exocyst octameric complex

A multi-subunit protein complex (composed of eight subunits) that is recruited to sites of active exocytosis where it facilitates the tethering of secretory vesicles to the plasma membrane prior to fusion.

Fenton chemistry

The catalytic decomposition of hydrogen peroxide (H2O2) into a hydroxide ion (OH−) and a hydroxyl radical (HO•) by ferrous iron; named after the British chemist H. J. H. Fenton (1854–1929).

Hepatic stellate cells

(HSCs). Liver cells located between liver sinusoidal endothelial cells (LSECs) and hepatocytes that store vitamin A when quiescent. In response to liver damage, HSCs become activated and produce extracellular matrix proteins that promote liver fibrogenesis.

Intermediary metabolism

The sum of anabolic and catabolic reactions that provide cells with metabolic energy, reducing power and biosynthetic intermediates.

Kupffer cells

Hepatic macrophages residing in the liver sinusoids, whose function includes breaking down red blood cells (RBCs) by phagocytosis in order to recycle the iron contained in haemoglobin.

L-type and T-type calcium channels

(Long-lasting-type and transient-type calcium channels). Voltage-dependent channels that allow calcium ions to flow into excitable cells, resulting in muscle contraction, neuron excitation, neurotransmitter release or gene regulation.

Membrane–organelle-based secretion

An unconventional mode of protein secretion in which cargo proteins lacking signal peptides are incorporated into membrane intermediates derived from lysosomes, endosomes or the autophagy machinery and released into the extracellular space after exocytosis.

Reticuloendothelial system

A heterogeneous population of phagocytic cells (mainly monocytes and macrophages) whose function includes the removal of foreign particles or old or damaged cells from the circulation.

Toll-like receptors

(TLRs). Single-pass membrane receptors that recognize molecules from infectious agents or endogenous damage signals and activate a signalling cascade stimulating immune cell responses.

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Galy, B., Conrad, M. & Muckenthaler, M. Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol 25, 133–155 (2024). https://doi.org/10.1038/s41580-023-00648-1

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