Ferroptosis in Liver Diseases: An Overview
Abstract
:1. Introduction
2. Discovery of Ferroptosis
3. An Overview of Ferroptosis
4. Mechanisms of Ferroptosis
- glutathione/glutathione peroxidase 4 (GSH/GPX4) pathway, inhibition of system Xc−, sulfur transfer pathway, and p53 regulatory axis;
- iron metabolism with the regulation of autophagy protein 5 and 7 (ATG5-ATG7) and nuclear receptor coactivator 4 (NCOA4) pathway and iron-responsive element-binding protein 2 (IREB2) related to ferritin metabolism, and the p62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor (Nrf2) regulatory pathways [3]; and
- lipid metabolism pathways as p53, arachidonate lipoxygenase 15 (ALOX15), acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3) [3].
4.1. Radical Oxygen Species (ROS)
4.2. Regulation of Ferroptosis via Cysteine-Glutathione Redox Axis
4.2.1. Biosynthesis of Glutathione
4.2.2. Uptake of Cysteine
4.2.3. System Xc−
4.2.4. Cysteine Synthesis via the Transsulfuration Pathway
4.3. The Enzyme Glutathione Peroxidase 4 and Ferroptosis
4.4. Lipid Metabolism and Ferroptosis
4.4.1. Role of Lipoxygenases
4.4.2. Lipid Peroxidation
4.4.3. Where Does Lipid Peroxidation Take Place?
4.5. Iron Metabolism and Ferroptosis
4.6. p53-Mediated Ferroptosis
4.7. Ferroptosis and the Keap1–Nrf2 Pathway
4.8. Other Related Signaling Pathways
5. Crosstalk between Autophagy and Ferroptosis
6. Pharmacological Modulation of Ferroptosis
6.1. Ferroptosis Inducers
6.2. Ferroptosis Inhibitors
7. Ferroptosis in Liver Diseases
7.1. Ferroptosis and Drug-Induced Liver Injury
7.2. Ferroptosis and Ischemia–Reperfusion Injury (IRI)
7.3. Chronic Liver Diseases (CLD)
7.4. Hepatocellular Carcinoma (HCC)
8. Conclusion and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
4-HNE | 4-hydroxy-noenal |
AA | Arachidonic acid |
ACC | Acetyl-CoA carboxylase |
ACSL4 | Acyl-CoA synthetase long-chain family member 4 |
ALD | Acute liver disease |
ALOXs | Arachidonate lipoxygenases |
AREs | Antioxidant response elements |
ATG5-7 | Aumiddlehagy protein 5 and 7 |
bZIP | Basic leucine zipper |
CBS | Cystathionine β-synthase |
CDKN1A/p21 | Cyclin-dependent kinase inhibitor 1A |
CISD1 | CDGSH iron sulfur domain 1 |
CLD | Chronic liver disease |
CoQ10 | Coenzyme Q10 |
CRC | Colorectal cancer |
DAMPs | Damage-associated molecular patterns |
DCYTB | Duodenal cytochrome B reductase |
DFO | Deferoxamine |
DILI | Drug-induced liver injury |
DMT1 | Divalent metal transporter 1 |
DPP4 | Dipeptidyl-peptidase 4 |
ER | Endoplasmic reticulum |
Fe2+ | Ferrous iron |
Fe3+ | Ferric iron |
FECH | Ferrochelatase |
Fer-1 | Ferrostatin-1 |
FPN | Ferroportin |
FSP1 | Ferroptosis suppressor protein 1 |
FTH1 | Ferritin heavy chain |
FTL | Ferritin light chain |
GGT | γ-Glutamyl transpeptidase |
GLC | γ-Glu-Cys-ligase |
GPX4 | Glutathione peroxidase 4 |
GSR | Glutathione reductase |
GSH | Glutathione |
GSS | Glutathione synthetase |
HATs | Heterodimeric amino acid transporters |
HCC | Hepatocellular carcinoma |
HCP-1 | Heme carrier protein-1 |
HO-1 | Heme oxygenase-1 |
HSC | Hemamiddleoietic Stem Cell |
HSPs | Heat shock proteins |
HSPB1 | Heat shock factor-binding protein 1 |
IREB2 | Iron-responsive element-binding protein 2 |
IRI | Ischemia–reperfusion injury |
Keap1 | Kelch-like ECH-associated protein 1 |
LC3-I/II | Microtubule-associated protein light chain 3 |
LIP | Labile iron pool |
Lip-1 | Liproxstatin-1 |
LPCAT3 | Lysophosphatidylcholine acyltransferase 3 |
MAPKs | Mitogen-activated protein kinases |
MDA | Malondialdehyde |
MRP/ABCC | Multidrug resistance-associated proteins |
MT-1G | Metallothionein-1G |
NAFLD | Non-alcoholic liver disease |
NAPQI | N-acetyl-p-benzoquinone imine |
NASH | Non-alcoholic steatohepatitis |
NCOA4 | Nuclear receptor coactivator 4 |
Nrf2 | Nuclear factor erythroid 2-related factor |
OMM | Outer mitochondrial membrane |
OXPHOS | Oxidative phosphorylation |
PARP1 | Poly [ADP-ribose] polymerase 1 |
PC | Phosphatidylcholine |
PE | Phosphatidylethanolamine |
PEPT1-2 | Proton-coupled oligopeptide transporter family members 1 and 2 |
PKC | Protein kinase C |
PS | Phosphatidylserine |
PUFAs | Polyunsaturated fatty chains |
Rb | Retinoblastoma |
RCD | Regulated cell death |
ROS | Reactive oxygen species |
RPTECs | Renal proximal tubular epithelial cells |
RSL3/5 | Ras-selective lethal small molecule 3/5 |
RTA | Radical-trapping antioxidant |
SAS | Sulfasalazine |
SAT1 | Spermidine/spermine N1-acetyltransferase 1 |
SOD3 | Superoxide dismutase 3 |
STEAP3 | Six-transmembrane epithelial antigen of prostate 3 |
Tf | Transferrin |
TGFβ | Transforming growth factor beta |
TRF1 | Transferrin receptor protein 1 |
TXN | Thioredoxin |
TXNRD1 | Thioredoxin reductase 1 |
VDACs | Voltage-dependent anion channels |
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Cell Death | Morphological Features | Biochemical Features |
---|---|---|
Ferroptosis | No rupture of the plasma membrane [3] Rounding up of the cell [3] Small mitochondria, outer mitochondrial rupture, reduction of the cristae [3] Normal nuclear size and no chromatin condensation [3] | Iron and ROS overload Activation of MAPKs Inhibition of system Xc− and decreased cystine uptake GSH depletion Release of arachidonic acid mediators [3] |
Apoptosis | Plasma membrane blebbing [3] Rounding up of the cell [3] Pseudopod retraction and reduction of cellular and nuclear volume [3] Nuclear fragmentation, chromatin condensation Formation of apoptotic bodies [3] No significant changes in mitochondrial structure [3] | Activation of caspases Oligonucleosomal DNA fragmentation PS exposure [3] |
Necroptosis | Rupture of the plasma membrane [3] Cytoplasmic swelling [3] Moderate chromatin condensation [5] Spillage of cellular constituents into microenvironment [3] | Decrease in ATP level Release DAMPs PARP1 hyperactivation [3] |
Autophagy | Lack of change in the plasma membrane [3] Accumulation of autophagic vacuoles [3] Lack of chromatin condensation [5] Formation of double-membraned autolysosomes, including macroautophagy, microautophagy and chaperone-mediated autophagy [3] | LC3-I to LC3-II conversion [3] Substrate degradation [5] |
Class | Class Characteristics | Impact on Ferroptosis | Compound Examples | Suitable for In Vivo Use |
---|---|---|---|---|
Class 1 | Inhibition of system Xc− | Prevention of cystine import, GSH depletion, loss of GPX4 activity | Erastin, sulfasalazine, sorafenib | Sorafenib, sulfasalazine |
Class 2 | Direct inhibition of GPX4 | Covalent interaction with GPX4 and inhibition of the enzyme | RSL3, RSL5 | No |
Class 3 | Depletion of GPX4 protein and CoQ10 | Depletion of GPX4 and CoQ10 | FIN56 | Unknown |
Class 4 | Induction of lipid peroxidation | Oxidation of iron drives lipid peroxidation and indirect inactivation of GPX4 | FINO2 | Unknown |
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Capelletti, M.M.; Manceau, H.; Puy, H.; Peoc’h, K. Ferroptosis in Liver Diseases: An Overview. Int. J. Mol. Sci. 2020, 21, 4908. https://doi.org/10.3390/ijms21144908
Capelletti MM, Manceau H, Puy H, Peoc’h K. Ferroptosis in Liver Diseases: An Overview. International Journal of Molecular Sciences. 2020; 21(14):4908. https://doi.org/10.3390/ijms21144908
Chicago/Turabian StyleCapelletti, Martina Maria, Hana Manceau, Hervé Puy, and Katell Peoc’h. 2020. "Ferroptosis in Liver Diseases: An Overview" International Journal of Molecular Sciences 21, no. 14: 4908. https://doi.org/10.3390/ijms21144908