Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Ironing out the details of ferroptosis

Nature Cell Biology volume 26, pages 1386–1393 (2024)Cite this article

Subjects

Abstract

Ferroptosis, spurred by excess labile iron and lipid peroxidation, is implicated in various diseases. Advances have been made in comprehending the lipid-peroxidation side of ferroptosis, but the exact role of iron in driving ferroptosis remains unknown. Although iron overload is characterized in multiple disease states, the potential role of ferroptosis within them remains undefined. This overview focuses on the ‘ferro’ side of ferroptosis, highlighting iron dysregulation in human diseases and potential therapeutic strategies targeting iron regulation and metabolism.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Biological functions of iron.
Fig. 2: Iron homeostasis regulation.
Fig. 3: Antioxidant enzymes in ferroptosis defence.

Similar content being viewed by others

References

  1. Aisen, P., Enns, C. & Wessling-Resnick, M. Chemistry and biology of eukaryotic iron metabolism. Int. J. Biochem. Cell Biol. 33, 940–959 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Ponka, P., Tenenbein, M. & Eaton, J. W. in Handbook on the Toxicology of Metals 4th edn (eds. Nordberg, G. F. et al.) Vol. 2, 879–902 (Elsevier, 2015).

  3. Hentze, M. W., Muckenthaler, M. U. & Andrews, N. C. Balancing acts: molecular control of mammalian iron metabolism. Cell 117, 285–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Weiss, G. & Goodnough, L. T. Anemia of chronic disease. N. Engl. J. Med. 352, 1011–1023 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Hentze, M. W., Muckenthaler, M. U., Galy, B. & Camaschella, C. Two to tango: regulation of mammalian iron metabolism. Cell 142, 24–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Andrews, N. C. Disorders of iron metabolism. N. Engl. J. Med. 341, 1986–1995 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Lill, R. Function and biogenesis of iron-sulphur proteins. Nature 460, 831–838 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Rouault, T. A. Mammalian iron-sulphur proteins: novel insights into biogenesis and function. Nat. Rev. Mol. Cell Biol. 16, 45–55 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Jordan, A. & Reichard, P. Ribonucleotide reductases. Annu. Rev. Biochem. 67, 71–98 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Rudolf, J., Makrantoni, V., Ingledew, W. J., Stark, M. J. & White, M. F. The DNA repair helicases XPD and FancJ have essential iron-sulfur domains. Mol. Cell 23, 801–808 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Gray, N. K. & Hentze, M. W. Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs. EMBO J. 13, 3882–3891 (1994).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Rouault, T. A. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat. Chem. Biol. 2, 406–414 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Kortman, G. A., Raffatellu, M., Swinkels, D. W. & Tjalsma, H. Nutritional iron turned inside out: intestinal stress from a gut microbial perspective. FEMS Microbiol. Rev. 38, 1202–1234 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Nemeth, E. & Ganz, T. Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323–342 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Drakesmith, H. & Prentice, A. M. Hepcidin and the iron-infection axis. Science 338, 768–772 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Donovan, A. et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403, 776–781 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Hellman, N. E. & Gitlin, J. D. Ceruloplasmin metabolism and function. Annu. Rev. Nutr. 22, 439–458 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Harris, Z. L., Durley, A. P., Man, T. K. & Gitlin, J. D. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl Acad. Sci. USA 96, 10812–10817 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Shayeghi, M. et al. Identification of an intestinal heme transporter. Cell 122, 789–801 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Conrad, M. E. & Umbreit, J. N. Iron absorption and transport-an update. Am. J. Hematol. 64, 287–298 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. McKie, A. T. et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell 5, 299–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Gunshin, H. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–488 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Muckenthaler, M. U., Galy, B. & Hentze, M. W. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev. Nutr. 28, 197–213 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Ohgami, R. S., Campagna, D. R., McDonald, A. & Fleming, M. D. The Steap proteins are metalloreductases. Blood 108, 1388–1394 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Arosio, P. & Levi, S. Ferritin, iron homeostasis, and oxidative damage. Free Radic. Biol. Med 33, 457–463 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. 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 Central  PubMed  Google Scholar 

  29. 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 

  30. Diao, J. et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520, 563–566 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Itakura, E., Kishi-Itakura, C. & Mizushima, N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256–1269 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2, 43ra56 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  34. 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 Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Doll, S. & Conrad, M. Iron and ferroptosis: a still ill-defined liaison. IUBMB Life 69, 423–434 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. 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 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Nakamura, T. et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371–377 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Mao, C., Liu, X., Yan, Y., Olszewski, K. & Gan, B. Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E19–E23 (2023).

    Article  CAS  PubMed  Google Scholar 

  44. Mishima, E. et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619, E9–E18 (2023).

    Article  CAS  PubMed  Google Scholar 

  45. Mao, C. et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593, 586–590 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Dixon, S. J. et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 3, e02523 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  47. Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).

    Article  CAS  PubMed  Google Scholar 

  48. Torti, S. V. & Torti, F. M. Iron and cancer: 2020 vision. Cancer Res. 80, 5435–5448 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Xue, Q. et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy 19, 1982–1996 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Chiabrando, D., Vinchi, F., Fiorito, V., Mercurio, S. & Tolosano, E. Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. Front. Pharm. 5, 61 (2014).

    Article  Google Scholar 

  51. Torti, S. V. & Torti, F. M. Iron and cancer: more ore to be mined. Nat. Rev. Cancer 13, 342–355 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Kumar, S. & Bandyopadhyay, U. Free heme toxicity and its detoxification systems in human. Toxicol. Lett. 157, 175–188 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Papanikolaou, G. & Pantopoulos, K. Iron metabolism and toxicity. Toxicol. Appl. Pharmacol. 202, 199–211 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Bacon, B. R. et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54, 328–343 (2011).

    Article  PubMed  Google Scholar 

  56. Anderson, G. J. & Frazer, D. M. Current understanding of iron homeostasis. Am. J. Clin. Nutr. 106, 1559S–1566S (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  57. Bridle, K. R. et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 361, 669–673 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Kowdley, K. V. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127, S79–S86 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Fernandez-Real, J. M. et al. Blood letting in high-ferritin type 2 diabetes: effects on vascular reactivity. Diabetes Care 25, 2249–2255 (2002).

    Article  PubMed  Google Scholar 

  60. Wood, J. C. Cardiac iron across different transfusion-dependent diseases. Blood Rev. 22, S14–S21 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. 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 

  62. Fang, X. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 2672–2680 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Dixon, S. J. & Stockwell, B. R. The role of iron and reactive oxygen species in cell death. Nat. Chem. Biol. 10, 9–17 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, H. et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66, 449–465 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Devos, D. et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid. Redox Signal. 21, 195–210 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Ayton, S., Lei, P. & Bush, A. I. Metallostasis in Alzheimer’s disease. Free Radic. Biol. Med. 62, 76–89 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Conrad, M., Angeli, J. P., Vandenabeele, P. & Stockwell, B. R. Regulated necrosis: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 15, 348–366 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Kontoghiorghe, C. N. & Kontoghiorghes, G. J. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes. Drug Des. Devel. Ther. 10, 465–481 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Spangler, B. et al. A reactivity-based probe of the intracellular labile ferrous iron pool. Nat. Chem. Biol. 12, 680–685 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Muir, R. K. et al. Measuring dynamic changes in the labile iron pool in vivo with a reactivity-based probe for positron emission tomography. ACS Cent. Sci. 5, 727–736 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Institutes of Health (R35ES031575).

Author information

Authors and Affiliations

  1. Center for Inflammation Science and Systems Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA

    Donna D. Zhang

Authors
  1. Donna D. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donna D. Zhang.

Ethics declarations

Competing interests

The author declares no competing interests.

Peer review

Peer review information

Nature Cell Biology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, D.D. Ironing out the details of ferroptosis. Nat Cell Biol 26, 1386–1393 (2024). https://doi.org/10.1038/s41556-024-01361-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41556-024-01361-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing