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Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney

Nature Reviews Nephrology volume 19, pages 315–336 (2023)Cite this article

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Abstract

Ferroptosis is a mechanism of regulated necrotic cell death characterized by iron-dependent, lipid peroxidation-driven membrane destruction that can be inhibited by glutathione peroxidase 4. Morphologically, it is characterized by cellular, organelle and cytoplasmic swelling and the loss of plasma membrane integrity, with the release of intracellular components. Ferroptosis is triggered in cells with dysregulated iron and thiol redox metabolism, whereby the initial robust but selective accumulation of hydroperoxy polyunsaturated fatty acid-containing phospholipids is further propagated through enzymatic and non-enzymatic secondary mechanisms, leading to formation of oxidatively truncated electrophilic species and their adducts with proteins. Thus, ferroptosis is dependent on the convergence of iron, thiol and lipid metabolic pathways. The kidney is particularly susceptible to redox imbalance. A growing body of evidence has linked ferroptosis to acute kidney injury in the context of diverse stimuli, such as ischaemia–reperfusion, sepsis or toxins, and to chronic kidney disease, suggesting that ferroptosis may represent a novel therapeutic target for kidney disease. However, further work is needed to address gaps in our understanding of the triggers, execution and spreading mechanisms of ferroptosis.

Key points

  • Multiple cell death pathways contribute to the pathogenesis of acute and chronic kidney injury; ferroptosis is one such mechanism of regulated necrotic cell death, characterized by marked oxidation of phospholipids containing polyunsaturated fatty acids.

  • Ferroptotic death programs are triggered in cells with dysregulated iron and thiol redox metabolism, leading to robust but selective lipid peroxidation, which is propagated through enzymatic and non-enzymatic mechanisms.

  • The excessive accumulation of hydroperoxy-derivatives of arachidonoyl- and adrenoyl-phosphatidylethanolamines is catalysed by a complex of 15-lipoxygenase with phosphatidylethanolamine-binding protein 1 and represents a potential therapeutic target.

  • GPX4 detoxifies phospholipid hydroperoxides to non-toxic phospholipid alcohols using glutathione as a source of reducing equivalents, thus preventing ferroptotic cell death.

  • iNOS, NO•, Ca2+-independent phospholipase A2β and FSP1 can eliminate ferroptotic lipid peroxidation products and prevent ferroptosis in cells that lack GPX4 catalytic activity.

  • Increased levels of urinary ferroptotic phospholipid hydroperoxides are associated with non-recovery of kidney function in patients with acute kidney injury.

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Fig. 1: Three pillars of the canonical ferroptosis pathway.
Fig. 2: Major pathways involved in the generation of pro-ferroptotic and anti-ferroptotic reactive radical intermediates.
Fig. 3: Systemic iron handling and regulation.
Fig. 4: Handling of intracellular iron and its role in ferroptosis.
Fig. 5: PUFA glycerophospholipids and their mechanisms of peroxidation.
Fig. 6: Metabolic network of major pathways involved in the execution and regulation of ferroptosis.
Fig. 7: Thiol metabolism and ferroptosis.

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Acknowledgements

The work of the authors is supported by the NIH (R01GM122923 to S.J.D.; U01AI156924, P01HL114453, R01CA165065, R01CA266342 and R01AI145406 to V.E.K.; R01NS076511, R37NS061817 and U01AI156923 to H.B.; and UG3DK114861 to J.A.K.) and by the American Cancer Society (RSG-21-017-01-CCG to S.J.D.).

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  1. Hülya Bayır

    Present address: Department of Pediatrics, Division of Critical Care and Hospital Medicine, Redox Health Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

Authors and Affiliations

  1. Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA

    Hülya Bayır & John A. Kellum

  2. Center for Free Radical and Antioxidant Health, Departments of Environmental Health, Pharmacology and Chemical Biology, Chemistry, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA

    Hülya Bayır, Yulia Y. Tyurina & Valerian E. Kagan

  3. Department of Biology, Stanford University, Stanford, CA, USA

    Scott J. Dixon

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H.B. and V.E.K. designed and conceptualized the review. All authors contributed to writing of the manuscript and reviewed and/or edited the manuscript before submission.

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Competing interests

S.J.D. is a founder of Prothegen Inc., a member of the scientific advisory board for Ferro Therapeutics and Hillstream BioPharma, and an inventor on patents related to ferroptosis (patent numbers 10597381, 10233171 and 9580398). J.A.K. is currently Chief Medical Officer of Spectral Medical and Dialco Medical Inc. The other authors declare no competing interests.

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Bayır, H., Dixon, S.J., Tyurina, Y.Y. et al. Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney. Nat Rev Nephrol 19, 315–336 (2023). https://doi.org/10.1038/s41581-023-00689-x

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