Abstract
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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Abbreviations
- AA:
-
arachidonic acid
- ACC1:
-
acetyl-CoA carboxylase alpha
- ACSF2:
-
andacyl-CoA synthetase family member 2
- ACSL4:
-
acyl-CoA synthetase long-chain family member 4
- AOA:
-
aminooxyacetic acid
- AKF:
-
acute kidney failure
- ATP5G3:
-
ATP synthase F0 complex subunit C3
- BSO:
-
buthionine sulfoximine
- BHT:
-
butylated hydroxytoluene
- CARS:
-
cysteinyl-tRNA synthetase
- CHAC1:
-
cation transport regulator-like protein 1
- COX-2:
-
cyclooxygenase-2
- CS:
-
citrate synthase
- CSSG:
-
cysteine-glutathione disulfide
- DAMP:
-
damage-associated molecular pattern molecule
- DMT1:
-
divalent metal transporter 1
- ER:
-
endoplasmic reticulum
- Fe3+:
-
ferric iron
- Fe2+:
-
ferrous iron
- FIN:
-
ferroptosis-inducing agents
- FLT-3:
-
fms-like tyrosine kinase 3
- FTH1:
-
ferritin heavy chain 1
- FTL:
-
ferritin light chain
- GPX4:
-
glutathione peroxidase 4
- GSH:
-
glutathione
- HMGB1:
-
high mobility group box 1
- HD:
-
Huntington’s disease
- HETE:
-
hydroxyeicosatetraenoic acid
- HO-1:
-
heme oxygenase-1
- HPETE:
-
hydroperoxyeicosatetraenoic acid
- HSF-1:
-
heat shock factor-1
- HSPB1:
-
heat shock protein beta-1
- HCC:
-
hepatocellular carcinoma
- IREB2:
-
iron-responsive element-binding protein 2
- JNK:
-
c-Jun NH2-terminal kinase
- Keap1:
-
Kelch-like ECH-associated protein 1
- LOX:
-
lipoxygenases
- LPCAT3:
-
lysophosphatidylcholine acyltransferase 3
- MAPK:
-
mitogen-activated protein kinase
- MDM2:
-
murine double minute-2
- MEFs:
-
mouse embryonic fibroblasts
- NADPH:
-
nicotinamide adenine dinucleotide phosphate
- NAPQI:
-
N-acetyl-p-benzoquinone imine
- NOX:
-
NADPH oxidase
- NRF2:
-
nuclear factor erythroid 2-related factor 2
- OLs:
-
oligodendrocytes
- PDAC:
-
pancreatic ductal adenocarcinoma
- PGSK:
-
phen green SK
- PKC:
-
protein kinase C
- PPP:
-
pentose phosphate pathway
- PTGS:
-
prostaglandin-endoperoxide synthase
- PUFAs:
-
polyunsaturated fatty acids
- PVL:
-
periventricular leukomalacia
- RCD:
-
regulated cell death
- ROS:
-
reactive oxygen species
- RPL8:
-
ribosomal protein L8
- RSLs:
-
Ras-selective lethal small molecules
- SCP2:
-
sterol carrier protein 2
- TFR1:
-
transferrin receptor 1
- TTC35:
-
tetratricopeptide repeat domain 35
- VDAC:
-
mitochondrial voltage-dependent anion channel.
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Acknowledgements
We apologize to the researchers who were not referenced owing to space limitations. We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by the National Institutes of Health of the USA (R01CA160417 and R01GM115366 to DT), The National Natural Science Foundation of China (31171229 and U1132005 to XS), and a Science and Information Technology of Guangzhou Key Project (201508020258 and 201400000003/4 to XS).
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Xie, Y., Hou, W., Song, X. et al. Ferroptosis: process and function. Cell Death Differ 23, 369–379 (2016). https://doi.org/10.1038/cdd.2015.158
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DOI: https://doi.org/10.1038/cdd.2015.158
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