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Targeting ferroptosis as a vulnerability in cancer

Abstract

Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.

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Fig. 1: Ferroptosis-driving and ferroptosis defence mechanisms.
Fig. 2: Ferroptosis as a vulnerability in cancer.
Fig. 3: Role of ferroptosis in antitumour immunity.

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Acknowledgements

We thank Amy Ninetto from the Research Medical Library at MD Anderson, for editing the manuscript, and apologize to colleagues whose work cannot be cited in this manuscript due to space limitations. B.G. is supported by The University of Texas MD Anderson Cancer Center, Emerson Collective Cancer Research Fund, and grants R01CA181196, R01CA244144 and R01CA247992 from the National Institutes of Health. The research from the authors’ lab has also been supported by the National Institutes of Health Cancer Center Support Grant P30CA016672 to The University of Texas MD Anderson Cancer Center.

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G.L. and B.G. researched data for the article and contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Boyi Gan.

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B.G. is an inventor on patent applications involving targeting ferroptosis in cancer therapy. G.L. and L.Z. declare no competing interests.

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Glossary

Cristae

Folds of the inner mitochondrial membrane that extend into the matrix of a mitochondrion.

Ferroptosis inducers

(FINs). A compound or treatment that can induce ferroptosis by boosting ferroptosis-promoting mechanisms and/or suppressing ferroptosis defence mechanisms.

Polyunsaturated fatty acid

(PUFA). A fatty acid that contains more than one double bond and is required for cellular signalling and membrane fluidity.

Peroxisomes

Organelles that are important for β-oxidation of very-long-chain fatty acids and synthesis of ether phospholipids.

Fenton reaction

A non-enzymatic reaction of labile iron and H2O2 that generates hydroxide and hydroxyl radicals, which can subsequently induce lipid peroxidation.

Anaplerotic reactions

Metabolic reactions that replenish the supply of intermediates involved in the citric acid cycle.

GPX

A family of peroxidases that use reduced glutathione as their cofactor to reduce hydroperoxide species to their corresponding alcohols.

System xc

An antiporter that imports cystine and exports glutamate; it consists of two subunits, including the transporter subunit SLC7A11 and the regulatory subunit SLC3A2.

Ubiquinone

Also known as coenzyme Q or CoQ. A lipophilic molecule that is composed of a quinone head group linked to a polyisoprenoid lipid tail and acts as an electron transport carrier in mitochondria.

Ubiquinol

(CoQH2). The fully reduced form of ubiquinone.

Dihydroorotate dehydrogenase

(DHODH). An inner mitochondrial membrane-localized enzyme that oxidizes dihydroorotate to orotate for pyrimidine synthesis while reducing CoQ to CoQH2.

Hypercholesterolaemia

High levels of cholesterol in the blood.

Lipid droplets

Organelles with a phospholipid monolayer that are responsible for lipid storage, including PUFA storage.

Iron–sulfur clusters

(ISCs). Molecular ensembles of iron and sulfur that function as protein co-factors to regulate iron homeostasis and redox reactions in response to oxidative stress.

Mevalonate pathway

A metabolic pathway that synthesizes cholesterol, CoQ and steroid hormones.

Epithelial-to-mesenchymal transition

(EMT). A process by which epithelial cells gradually lose their cell polarity and intercellular adhesion properties and acquire mesenchymal-like phenotypes, including migratory and invasive properties.

Cyst(e)inase

Engineered enzymes that degrade extracellular cysteine and cystine.

Transsulfuration pathway

A metabolic pathway that transfers sulfur from homocysteine to cysteine, leading to cysteine biosynthesis.

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Lei, G., Zhuang, L. & Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 22, 381–396 (2022). https://doi.org/10.1038/s41568-022-00459-0

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