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Cited by 2,099Ferroptosis and cancer prognosisIron Metabolism and DisordersCell death mechanisms and regulation

Ferroptosis: machinery and regulation

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Chen, Xin, Li, Jingbo, Kang, Rui, Klionsky, Daniel J., Tang, Daolin·2021·Autophagy
DOI 10.1080/15548627.2020.1810918PMC PMC8496712
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Abstract

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which is controlled by integrated oxidation and antioxidant systems. The iron-containing enzyme lipoxygenase is the main promoter of ferroptosis by producing lipid hydroperoxides, and its function relies on the activation of ACSL4-dependent lipid biosynthesis. In contrast, the selenium-containing enzyme GPX4 is currently recognized as a central repressor of ferroptosis, and its activity depends on glutathione produced from the activation of the cystine-glutamate antiporter SLC7A11. Many metabolic (especially involving iron, lipids, and amino acids) and degradation pathways (macroautophagy/autophagy and the ubiquitin-proteasome system) orchestrate the complex ferroptotic response through direct or indirect regulation of iron accumulation or lipid peroxidation. Although the detailed mechanism of membrane injury during ferroptosis remains a mystery, ESCRT III-mediated plasma membrane repair can make cells resistant to ferroptosis. Here, we review the recent rapid progress in understanding the molecular mechanisms of ferroptosis and focus on the epigenetic, transcriptional, and posttranslational regulation of this process.Abbreviations: 2ME: beta-mercaptoethanol; α-KG: α-ketoglutarate; ccRCC: clear cell renal cell carcinoma; EMT: epithelial-mesenchymal transition; FAO: fatty acid beta-oxidation; GSH: glutathione; MEFs: mouse embryonic fibroblasts; MUFAs: monounsaturated fatty acids; NO: nitric oxide; NOX: NADPH oxidase; PPP: pentose phosphate pathway; PUFA: polyunsaturated fatty acid; RCD: regulated cell death; RNS: reactive nitrogen species; ROS: reactive oxygen species; RTAs: radical-trapping antioxidants; UPS: ubiquitin-proteasome system; UTR: untranslated region.

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Authors
Chen, X., Li, J., Kang, R., Klionsky, D. J., & Tang, D.
Affiliations
  • Third Affiliated Hospital of Guangzhou Medical University (CN)
  • The University of Texas Southwestern Medical Center (US)
  • University of Michigan (US)
Corresponding author
Tang, Daolin
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2020-08-26
Volume
17
Issue
9
Pages
2054-2081
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.1080/15548627.2020.1810918
PMC
PMC8496712
OpenAlex
W3077764649
Cited by
2,099
References
31
Citations by year
2026: 341 · 2025: 503 · 2024: 544 · 2023: 425 · 2022: 194 · 2021: 73 · 2020: 17
FWCI
24.90
Type
journal article
Language
en
Open access
Locations
  • Autophagy (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01CA211070)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
ferroptosis, regulated cell death, lipid peroxidation, GPX4, ACSL4, SLC7A11, glutathione, iron metabolism, ubiquitin-proteasome system, ESCRT-III, membrane repair, epigenetic regulation, post-translational regulation, lipid hydroperoxides
MeSH terms
Ferroptosis, Animals, Autophagy, Fibroblasts, Oxidation-Reduction, Lipid Peroxidation, Reactive Oxygen Species, Mice

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