The development of the concept of ferroptosis

Hirschhorn, Tal; Stockwell, Brent R.

doi:10.1016/j.freeradbiomed.2018.09.043

Cited by 732 publications

(591 citation statements)

References 246 publications

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“…Compelling evidence supports the notion that the missing activity of GPx4 leads to a peculiar form of regulated cell death, named ferroptosis [11,12,26]. Although other constraints such as membrane fatty acid composition and iron availability must be fulfilled, it is the insufficient reduction of lipid hydroperoxides, from which lipid peroxidation is activated, which is the critical event priming ferroptosis [13,14].…”

Section: Discussionmentioning

confidence: 74%

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

et al. 2019

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Ras‐selective lethal small molecule 3 (RSL3), a drug candidate prototype for cancer chemotherapy, triggers ferroptosis by inactivating the glutathione peroxidase glutathione peroxidase 4 (GPx4). Here, we report the purification of the protein indispensable for GPx4 inactivation by RSL3. Mass spectrometric analysis identified 14‐3‐3 isoforms as candidates, and recombinant human 14‐3‐3ε confirms the identification. The function of 14‐3‐3ε is redox‐regulated. Moreover, overexpression or silencing of the gene coding for 14‐3‐3ε consistently controls the inactivation of GPx4 by RSL3. The interaction of GPx4 with a redox‐regulated adaptor protein operating in cell signaling further contributes to frame it within redox‐regulated pathways of cell survival and death and opens new therapeutic perspectives.

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Section: Discussionmentioning

confidence: 74%

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

et al. 2019

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“…An extensive literature, predating by decades the description of ferroptosis in 2012, links lipid peroxidation to cell death, tissue damage, and pathology (e.g., refs …”

Section: Gpx4 Lipid Peroxidation and Ferroptosis In Development Andmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+)‐dependent formation of toxic lipid reactive oxygen species (ROS). Inhibition of GPX4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. This review describes the formation of reactive lipid species, the function of GPX4 in preventing oxidative lipid damage, and the link between GPX4 dysfunction, lipid oxidation, and the induction of ferroptosis.

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“…The term ferroptosis describes the nonapoptotic, irondependent form of regulated cell death characterized by an accumulation of lethal lipid peroxides (9)(10)(11). Ferroptosis is triggered by a critical depletion of the antioxidant glutathione (GSH), or loss of lipid hydroperoxide repair systems.…”

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confidence: 99%

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

Leu

Murphy

George

2019

Proc. Natl. Acad. Sci. U.S.A.

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A population-restricted single-nucleotide coding region polymorphism (SNP) at codon 47 exists in the human TP53 gene (P47S, hereafter P47 and S47). In studies aimed at identifying functional differences between these variants, we found that the Africanspecific S47 variant associates with an impaired response to agents that induce the oxidative stress-dependent, nonapoptotic cell death process of ferroptosis. This phenotype is manifested as a greater resistance to glutamate-induced cytotoxicity in cultured cells as well as increased carbon tetrachloride-mediated liver damage in a mouse model. The differential ferroptotic responses associate with intracellular antioxidant differences between P47 and S47 cells, including elevated abundance of the low molecular weight thiols coenzyme A (CoA) and glutathione in S47 cells. Importantly, the disparate ferroptosis phenotypes related to the P47S polymorphism are reversible. Exogenous administration of CoA provides protection against ferroptosis in cultured mouse and human cells, as well as in a mouse model. The combined data support a positive role for p53 in ferroptosis and identify CoA as a regulator of this cell death process. Together, these findings provide mechanistic insight linking redox regulation of p53 to small molecule antioxidants and stress signaling pathways. They also identify potential therapeutic approaches to redox-related pathologies.p53 | coenzyme A | ferroptosis | S-thiolation | polymorphism

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The development of the concept of ferroptosis

Cited by 732 publications

References 246 publications

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

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