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Ferroptosis: process and function
Open accessAbstract
Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.
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“Ferroptosis is a form of RCD initiated by specific perturbations of the intracellular microenvironment, notably severe lipid peroxidation, which relies on ROS generation and iron availability [533–536].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [535]
In the citing paper
“It is morphologically and mechanistically distinct from apoptotic, necroptotic, and autophagic cell death (Xie et al., 2016).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Xie et al., 2016
In the citing paper
“Moreover, ferroptosis can be blocked with iron chelators but not with inhibitors of apoptosis and necroptosis (Xie et al., 2016).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Xie et al., 2016
In the citing paper
“Ferroptosis is an iron-dependent oxidative form of cell death associated with increased lipid peroxidation (Xie et al., 2016).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Xie et al., 2016
In the citing paper
“Ferroptosis is characterized by the accumulation of iron and malondialdehyde (MDA), and peroxidation of lipids; depletion of glutathione (GSH); and alteration in mitochondrial morphology, including decreased number of or diminished mitochondrial cristae and ruptured outer mitochondrial membranes (Dixon et al., 2012;Xie et al., 2016).”
From MiR-378a-3p/ SLC7A11 regulate ferroptosis in nerve injury induced by lead exposure (2022) · cites this paper as Xie et al., 2016
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Self-citation
Metadata
- Authors
- Xie, Y., Hou, W., Song, X., Yu, Y., Huang, J., Sun, X., Kang, R., & Tang, D.
- Affiliations
- Central South University (CN)
- University of Pittsburgh (US)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Corresponding author
- Kang, R
- Tang, D
- Venue
- Cell Death & Differentiation
- Published
- 2016-01-22
- Volume
- 23
- Issue
- 3
- Pages
- 369-379
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5072448
- OpenAlex
- W2265062179
- Cited by
- 3,727
- References
- 47
- Citations by year
- 2026: 295 · 2025: 482 · 2024: 644 · 2023: 618 · 2022: 588 · 2021: 470 · 2020: 284 · 2019: 157 · 2018: 94 · 2017: 60 · 2016: 30
- FWCI
- 19.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh
- National Natural Science Foundation of China (201508020258, R01GM115366, 201400000003, R01CA160417, 31171229, U1132005)
- National Institutes of Health
- National Cancer Institute (R01CA160417)
- National Institute of General Medical Sciences (R01GM115366)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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, reactive oxygen species, iron metabolism, GPX4, NADPH oxidase, p53, NF-E2-related factor 2, mitochondrial membrane damage, mitochondrial voltage-dependent anion channel, endoplasmic reticulum stress, iron chelators, ferroptosis inhibitors, cancer cell death, neurodegenerative diseases, drug-induced liver injury, ischemia-reperfusion injury, T cell immunity
- MeSH terms
- Animals, Humans, Iron, Iron Chelating Agents, Mitochondria, Lipid Peroxidation, Signal Transduction, Cell Death, Reactive Oxygen Species, Oxidative Stress, Endoplasmic Reticulum Stress
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