Abstract
The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
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Acknowledgements
X.J. is supported by National Institutes of Health (NIH) grants R01CA204232 and R01CA166413, a Memorial Sloan Kettering Cancer Center (MSKCC) Functional Genomic Initiative grant, as well as a National Cancer Institute (NCI) Cancer Centre core grant P30 CA008748 to MSKCC. B.R.S. is supported by NCI grants P01CA87497 and R35CA209896 and National Institute of Neurological Disorders and Stroke (NINDS) grant R61NS109407. M.C. is supported by the Deutsche Forschungsgemeinschaft (DFG) CO 291/5-2 and CO 291/7-1, the German Federal Ministry of Education and Research (BMBF) VIP+ programme NEUROPROTEKT (03VP04260), the Helmholtz Validation Fund (0042), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1933), the Else Kröner-Fresenius-Stiftung and the m4 Award provided by the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi). M.C. has further received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. GA 884754).
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X.J. is an inventor on patents and patent applications involving programmed cell death and autophagy. B.R.S. is an inventor on patents and patent applications involving ferroptosis, co-founded and serves as a consultant to Inzen Therapeutics and Nevrox Limited, and serves as a consultant to Weatherwax Biotechnologies Corporation. M.C. is an inventor on patents for some of the compounds described herein, and co-founder of ROSCUE Therapeutics GmbH.
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Glossary
- Lipid peroxidation
-
The oxidative destruction of lipids, whereby free radicals snitch electrons from polyunsaturated fatty acid residues in cellular membranes. This in turn leads to the formation of carbon-centred lipid radicals, which can initiate the lipid peroxidation chain reaction if not inhibited enzymatically or by lipophilic antioxidants.
- Iron–sulfur clusters
-
Small molecular structures consisting of iron and sulfur, which are mostly integrated into enzymes and larger protein complexes mediating electron transfer.
- Glutathione peroxidases
-
(GPXs). A family of structurally related enzymes that usually reduce hydrogen peroxide (H2O2) and other organic peroxides to water and alcohols, respectively, using mostly glutathione (GSH) as an electron donor.
- Glutathione-S-transferases
-
A large family of enzymes that catalyse the conjugation of the reduced form of glutathione (GSH) to xenobiotics (via a sulfhydryl group) for detoxification purposes.
- Thiol deprivation
-
A cellular condition marked by cysteine deprivation, causing glutathione (GSH) depletion and endoplasmic reticulum stress.
- Reactive oxygen species
-
(ROS). Partially reduced forms of oxygen, such as hydroperoxides, superoxide, singlet oxygen and hydroxyl radicals, that may oxidize and thereby destroy cellular components including lipids, protein and DNA.
- Selenoprotein
-
A protein into which the element selenium is co-translationally incorporated in the form of selenocysteine that usually constitutes the active site and is frequently involved in oxidative defence.
- Free radicals
-
Molecules with an unpaired electron in the outer orbit such as the hydroxyl radical and peroxyl radical, whereby they become generally unstable and highly reactive.
- Ischaemia–reperfusion
-
Organ tissue damage resulting from limited blood flow and oxygen deprivation followed by reintroduction of blood flow and oxygenation, causing oxygen radical formation, cell death and tissue detriment. Examples include ischaemic heart disease and ischaemic kidney failure.
- Fenton reaction
-
A chemical reaction between iron and hydrogen peroxide (H2O2) yielding the highly toxic free radicals, which in turn can spark lipid peroxidation.
- Cyclooxygenases
-
A family of two dedicated enzymes in mammals that oxygenate arachidonic acid to produce prostanoids that mediate numerous physiological processes including inflammation, angiogenesis and pain.
- Ferritin
-
An iron storage protein in cells that binds and sequesters intracellular iron in the form of ferric ion.
- Transferrin
-
A protein that transports iron into cells through receptor-mediated endocytosis.
- Anaplerotic metabolite
-
A metabolite that functions in the replenishment of certain metabolic pathways. For example, glutamine, through generating α-ketoglutarate, can replenish the tricarboxylic acid (TCA) cycle.
- Ubiquinone
-
A lipophilic metabolite (also known as coenzyme Q10) generated by the mevalonate pathway that widely acts by shuttling electrons in the mitochondrial respiratory chain.
- Mevalonate pathway
-
A lipid biosynthesis pathway that produces terpene-derived compounds such as cholesterol and ubiquinone.
- Isopentenylation
-
The post-transcriptional modification of base 37 in tRNA with isopentenyl leading to the formation of N6-isopentenyl adenosine (i6A).
- Pyroptosis
-
A form of inflammatory, non-apoptotic cell death mostly occurring in immune and epithelial cells, in response to conditions such as infection of intracellular pathogens; executed by membrane pore-forming gasdermin proteins after cleavage by caspase-containing inflammasome complex.
- Necroptosis
-
The first described form of regulated necrosis based on findings that TNFα not only triggers apoptosis but also necrosis under specific conditions in some cells. Necroptosis is mediated by the RIP3 kinase and MLKL, and is implicated in inflammation.
- Immune checkpoint blockade
-
The process of activating immune cells by inhibiting a signalling pathway that normally suppresses their activity; therapeutically, inhibiting cancer cell immune checkpoint enables the human immune system to eliminate cancer cells.
- Excitotoxic cell death
-
A form of neuronal cell death elicited by exposure of glutamate receptor-expressing neurons to excess glutamate or related excitatory amino acids.
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Jiang, X., Stockwell, B.R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22, 266–282 (2021). https://doi.org/10.1038/s41580-020-00324-8
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DOI: https://doi.org/10.1038/s41580-020-00324-8
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