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A guideline on the molecular ecosystem regulating ferroptosis

Nature Cell Biology (2024)Cite this article

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Abstract

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

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Fig. 1: Production of ROS in ferroptosis.
Fig. 2: Lipid resources for ferroptosis.
Fig. 3: Lipid peroxidation in ferroptosis.
Fig. 4: Enzymatic antioxidants in ferroptosis.

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Acknowledgements

The authors thank all of the pioneers in the field and our colleagues who contributed to the study of the process and function of ferroptosis. The lead contact D.T. is supported by grants from the US National Institutes of Health (R01CA160417, R01CA229275 and R01GM127791).

Author information

Authors and Affiliations

  1. Department of Oncology and Hematology, China–Japan Union Hospital of Jilin University, Changchun, China

    Enyong Dai

  2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China

    Xin Chen & Jinbao Liu

  3. Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany

    Andreas Linkermann

  4. Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    Andreas Linkermann

  5. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Xuejun Jiang

  6. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Rui Kang, Herbert J. Zeh & Daolin Tang

  7. Department of Environmental Health, University of Pittsburgh, Pittsburgh, PA, USA

    Valerian E. Kagan

  8. Department of Pediatrics, Columbia University, New York, NY, USA

    Hülya Bayir

  9. Department of Biological Sciences, St. John’s University, New York, NY, USA

    Wan Seok Yang

  10. Institute for Genetics, CECAD, University of Cologne, Cologne, Germany

    Ana J. Garcia-Saez

  11. Department of Physiology, University of Alberta, Edmonton, Alberta, Canada

    Maria S. Ioannou

  12. Cold Spring Harbor Laboratory, New York, USA

    Tobias Janowitz

  13. Department of Cell Systems and Anatomy, South Texas Veterans Health Care System, San Antonio, TX, USA

    Qitao Ran

  14. Institute for Cancer Genetics, and Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Wei Gu

  15. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Boyi Gan

  16. Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium

    Dmitri V. Krysko

  17. Cancer Research Institute Ghent, Ghent, Belgium

    Dmitri V. Krysko

  18. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China

    Xiaofeng Zhu

  19. Department of Clinical Laboratory, Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital and College of Medical Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiayi Wang

  20. Department of Nephrology and Hypertension, University Hospital Schleswig–Holstein, Kiel, Germany

    Stefan Krautwald

  21. Department of Pathology and Biological Response, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Shinya Toyokuni

  22. Center for Low-Temperature Plasma Sciences, Nagoya University, Nagoya, Japan

    Shinya Toyokuni

  23. Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, China

    Yangchun Xie

  24. Institute for Tumor Biology and Experimental Therapy, Georg–Speyer–Haus, Frankfurt am Main, Germany

    Florian R. Greten

  25. Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany

    Florian R. Greten

  26. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Florian R. Greten

  27. Houston Methodist Neal Cancer Center/Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA

    Qing Yi

  28. Genetics and Cellular Engineering Group, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany

    Joel Schick

  29. DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Jiao Liu

  30. AstraZeneca, Early Oncology R&D, Gaithersburg, MD, USA

    Dmitry I. Gabrilovich

  31. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA

    Donna D. Zhang

  32. Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China

    Minghua Yang

  33. Hunan Clinical Research Center of Pediatric Cancer, Changsha, China

    Minghua Yang

  34. Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli–Calmettes, Marseille, France

    Juan Iovanna

  35. Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland

    Manfred Kopf

  36. Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, and Metabolism, Medical University of Innsbruck, Innsbruck, Austria

    Timon E. Adolph

  37. Department of Molecular Genetics and Microbiology Center for Applied Genomic Technologies, Duke University, Durham, NC, USA

    Jen-Tsan Chi

  38. Department of Endoscopy Center, China–Japan Union Hospital of Jilin University, Changchun, China

    Changfeng Li

  39. Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Hidenori Ichijo

  40. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Michael Karin

  41. Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Vijay G. Sankaran

  42. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Vijay G. Sankaran

  43. Departments of Surgery and Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    Weiping Zou

  44. Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA

    Lorenzo Galluzzi

  45. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Lorenzo Galluzzi

  46. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA

    Lorenzo Galluzzi

  47. Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia

    Ashley I. Bush

  48. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Binghui Li

  49. Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China

    Binghui Li

  50. Department of Cancer Cell Biology and National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Binghui Li

  51. Department of Experimental Medicine, Tor Vergata University of Rome, Rome, Italy

    Gerry Melino

  52. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA

    Eric H. Baehrecke

  53. Departments of Surgery, Immunology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Michael T. Lotze

  54. Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA

    Daniel J. Klionsky

  55. Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA

    Brent R. Stockwell

  56. Equipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France

    Guido Kroemer

  57. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

    Guido Kroemer

  58. Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

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  1. Enyong Dai
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Corresponding authors

Correspondence to Enyong Dai, Brent R. Stockwell, Guido Kroemer or Daolin Tang.

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Competing interests

B.R.S. is an inventor on patents and patent applications involving ferroptosis, co-founded (and serves as a consultant to, ProJenX and Exarta Therapeutics, holds equity in Sonata Therapeutics and serves as a consultant to Weatherwax Biotechnologies Corporation and Akin Gump Strauss Hauer & Feld LLP. B.G. is an inventor on patent applications involving targeting ferroptosis in cancer therapy and reports personal fees from Guidepoint Global, Cambridge Solutions and NGM Bio. D.I.G. is an employee and shareholder of AstraZeneca. V.G.S. serves as an advisor to, and/or has equity, in Branch Biosciences, Ensoma and Cellarity (all unrelated to the present work). L.G. has/had research contracts with Lytix Biopharma, Promontory and Onxeo; received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation; and holds Promontory stock options. A.I.B. holds shares in Cogstate Ltd, Alterity Ltd and a profit share with Collaborative Medicinal Development LLC, and acts as a paid consultant to Collaborative Medicinal Development LLC. X.J. is an inventor of patents related to autophagy and cell death, and holds equity in, and also consults for, Exarta Therapeutics and Lime Therapeutics. G.K. has research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage; is on the Board of Directors of the Bristol Myers Squibb Foundation France; is a scientific cofounder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio; is on the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds; and is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. G.K.’s wife, L. Zitvogel, has held research contracts with GlaxoSmithKline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche; she was on the Board of Directors of Transgene, is a cofounder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer Ingelheim. The remaining authors declare no competing interests. The funders had no role in the writing of the manuscript.

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Dai, E., Chen, X., Linkermann, A. et al. A guideline on the molecular ecosystem regulating ferroptosis. Nat Cell Biol (2024). https://doi.org/10.1038/s41556-024-01360-8

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