The Mechanisms of Ferroptosis Under Hypoxia

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Abstract

Ferroptosis is a new form of programmed cell death, which is characterized by the iron-dependent accumulation of lipid peroxidation and increase of ROS, resulting in oxidative stress and cell death. Iron, lipid, and multiple signaling pathways precisely control the occurrence and implementation of ferroptosis. The pathways mainly include Nrf2/HO-1 signaling pathway, p62/Keap1/Nrf2 signaling pathway. Activating p62/Keap1/Nrf2 signaling pathway inhibits ferroptosis. Nrf2/HO-1 signaling pathway promotes ferroptosis. Furthermore, some factors also participate in the occurrence of ferroptosis under hypoxia, such as HIF-1, NCOA4, DMT1. Meanwhile, ferroptosis is related with hypoxia-related diseases, such as MIRI, cancers, and AKI. Accordingly, ferroptosis appears to be a therapeutic target for hypoxia-related diseases.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Broadening horizons: the role of ferroptosis in cancer

Xin CHEN, Rui Kang, Guido Kroemer … (2021)

The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.

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Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.

Wan Seok Yang, Katherine Kim, Michael M Gaschler … (2016)

Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts.

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Author and article information

Contributors

Shibo Sun:

ORCID: http://orcid.org/0000-0001-9287-1820

shibosunky@126.com

Journal

Journal ID (nlm-ta): Cell Mol Neurobiol

Journal ID (iso-abbrev): Cell Mol Neurobiol

Title: Cellular and Molecular Neurobiology

Publisher: Springer US (New York )

ISSN (Print): 0272-4340

ISSN (Electronic): 1573-6830

Publication date (Electronic): 17 July 2023

Publication date PMC-release: 17 July 2023

Publication date (Print): 2023

Volume: 43

Issue: 7

Pages: 3329-3341

Affiliations

[1 ]GRID grid.414902.a, ISNI 0000 0004 1771 3912, Department of Pulmonary and Critical Care Medicine, , First Affiliated Hospital, Kunming Medical University, ; No. 295, Xichang Road, Wuhua District, Kunming, 650032 China

[2 ]GRID grid.285847.4, ISNI 0000 0000 9588 0960, 2020 Clinical Medicine Class 6, , Kunming Medical University, ; Kunming, 650500 China

[3 ]GRID grid.285847.4, ISNI 0000 0000 9588 0960, Department of Cardiology, , The First Affiliated Hospital of Kunming Medical University, Kunming Medical University, ; Kunming, 650032 China

[4 ]GRID grid.414902.a, ISNI 0000 0004 1771 3912, Department of Cardiothoracic Surgery, , First Affiliated Hospital, Kunming Medical University, ; Kunming, 650032 China

Author information

Shibo Sun http://orcid.org/0000-0001-9287-1820

Article

Publisher ID: 1388

DOI: 10.1007/s10571-023-01388-8

PMC ID: 10477166

PubMed ID: 37458878

SO-VID: f4979775-33f1-4a3b-8169-5a905fc9d8d8

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 April 2023

Date accepted : 6 July 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82160007

Award Recipient : Shibo Sun

Funded by: FundRef http://dx.doi.org/10.13039/501100008871, Yunnan Provincial Science and Technology Department;

Award ID: 2019FE001 (-058)

Award Recipient : Shibo Sun

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ScienceOpen disciplines: Neurosciences

Keywords: ferroptosis,hypoxia,hypoxia-inducible factor,lipid peroxidation,system xc

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ScienceOpen disciplines: Neurosciences

Keywords: ferroptosis, hypoxia, hypoxia-inducible factor, lipid peroxidation, system xc

The Mechanisms of Ferroptosis Under Hypoxia

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Neuronal Signaling

Most cited references 137

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Broadening horizons: the role of ferroptosis in cancer

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.

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