GPX4 (Glutathione Peroxidase 4)
<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>GPX4</td></tr>
<tr><td><strong>UniProt</strong></td><td><a href="https://www.uniprot.org/uniprot/P36969">P36969</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>22 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytosol, Mitochondria, Nucleus</td></tr>
<tr><td><strong>PDB Structures</strong></td><td><a href="https://www.rcsb.org/structure/5L71">5L71</a>, <a href="https://www.rcsb.org/structure/2OBI">2OBI</a></td></tr>
<tr><td><strong>Aliases</strong></td><td>Phospholipid Hydroperoxide Glutathione Peroxidase, PHGPx</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1277 edges</a></td>
</tr>
</table>
</div>
Overview
...GPX4 (Glutathione Peroxidase 4)
<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>GPX4</td></tr>
<tr><td><strong>UniProt</strong></td><td><a href="https://www.uniprot.org/uniprot/P36969">P36969</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>22 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytosol, Mitochondria, Nucleus</td></tr>
<tr><td><strong>PDB Structures</strong></td><td><a href="https://www.rcsb.org/structure/5L71">5L71</a>, <a href="https://www.rcsb.org/structure/2OBI">2OBI</a></td></tr>
<tr><td><strong>Aliases</strong></td><td>Phospholipid Hydroperoxide Glutathione Peroxidase, PHGPx</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1277 edges</a></td>
</tr>
</table>
</div>
Overview
GPX4 (Glutathione Peroxidase 4), also known as phospholipid hydroperoxide glutathione peroxidase (PHGPx), is a unique member of the glutathione peroxidase family that directly reduces lipid hydroperoxides in cellular membranes. Unlike other GPX enzymes that require free hydrogen peroxide, GPX4 can reduce complex lipid hydroperoxides embedded within phospholipid bilayers, making it the master regulator of [ferroptosis](/entities/ferroptosis)—a regulated cell death pathway driven by iron-dependent lipid peroxidation.[@friedmann2014]
Structure and Domains
GPX4 is a 197-amino acid protein with a molecular weight of approximately 22 kDa. Unlike other selenoproteins, GPX4 contains a selenocysteine (Sec) residue at its active site (position 46 in humans), which is encoded by an in-frame UGA codon that normally signals translation termination.[@ingold2018]
Key structural features:
- Active site selenocysteine: Essential for the high catalytic efficiency of lipid hydroperoxide reduction
- Three functional isoforms: Cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), generated from alternative translation initiation sites
- SECIS element: A stem-loop structure in the 3' UTR required for selenocysteine incorporation
The crystal structure reveals a compact globular protein with the selenocysteine positioned in a surface-accessible pocket that accommodates phospholipid substrates.[@scheerer2007]
Normal Function
GPX4 serves as the primary defense against lipid peroxidation in cellular membranes:[@brigeliusfloh2013]
Lipid hydroperoxide reduction: Directly reduces lipid hydroperoxides (LOOH) to corresponding alcohols (LOH) using glutathione (GSH) as a cofactor
Ferroptosis suppression: Prevents the accumulation of oxidized phospholipids that trigger ferroptotic cell death
Sperm maturation: Essential for male fertility; mitochondrial GPX4 is a structural component of the sperm mitochondrial capsule
Redox signaling: Modulates lipid-derived signaling moleculesThe catalytic cycle involves:
GPX4-SeH + LOOH → GPX4-SeOH + LOH
GPX4-SeOH + GSH → GPX4-SeSG + H2O
GPX4-SeSG + GSH → GPX4-SeH + GSSG
Role in Neurodegeneration
Ferroptosis and Neurodegeneration
GPX4 dysfunction is increasingly recognized as central to neurodegenerative diseases through ferroptosis:[@stockwell2017]
Alzheimer's Disease:
- GPX4 expression is reduced in AD brain tissue
- Lipid peroxidation markers are elevated in AD patients and correlate with cognitive decline
- [Aβ](/proteins/amyloid-beta) oligomers can trigger ferroptosis by depleting glutathione
- GPX4 haplodeficiency accelerates Aβ pathology in mouse models[@hambright2017]
Parkinson's Disease:
- Iron accumulation in the substantia nigra creates conditions favorable for ferroptosis
- [α-Synuclein](/proteins/alpha-synuclein) aggregates can sequester GPX4, impairing its function
- GPX4 activators protect dopaminergic [neurons](/entities/neurons) in PD models
- GPX4 deficiency sensitizes neurons to ferroptotic death[@do2021]
Amyotrophic Lateral Sclerosis:
- GPX4 levels are decreased in spinal motor neurons of ALS patients
- SOD1 mutations increase susceptibility to ferroptosis
- GPX4 overexpression extends survival in ALS mouse models
Multiple Sclerosis:
- Ferroptosis contributes to oligodendrocyte death in MS lesions
- GPX4 expression is reduced in active demyelinating lesions
Molecular Mechanisms
The ferroptosis pathway involves several key players that intersect with GPX4:[@jiang2021]
Iron accumulation: Increases labile iron pool, promoting Fenton chemistry
Polyunsaturated fatty acids (PUFAs): Substrates for lipid peroxidation
System Xc-: Cystine/glutamate antiporter that supplies cysteine for GSH synthesis
FSP1/AIFM2: Parallel ferroptosis suppressor that acts independently of GPX4
NRF2: Transcriptional regulator of GPX4 and antioxidant genesTherapeutic Targeting
GPX4 Activation Strategies
Several approaches are being explored to enhance GPX4 function:[@chen2021]
| Strategy | Mechanism | Status |
|----------|-----------|--------|
| Selenocysteine supplementation | Supports GPX4 synthesis | Preclinical |
| GPX4 mimetics | Small molecule antioxidants | Research phase |
| Gene therapy | GPX4 overexpression | Preclinical models |
| GSH precursors (NAC, GSH-EE) | Provides cofactor | Clinical use |
Ferroptosis Inhibitors
Indirect approaches to support GPX4 function:[@zilka2017]
- Deferoxamine: Iron chelator that reduces lipid peroxidation
- Liproxstatin-1: Direct ferroptosis inhibitor
- Ferrostatin-1: Lipid radical scavenger
- Vitamin E: Lipid-soluble antioxidant
System Xc- Modulators
- Dimethyl fumarate: Activates NRF2, increases GSH synthesis
- Sulfasalazine: Inhibits System Xc- (caution: may promote ferroptosis)
Protein Interactions
| Interacting Partner | Function | Relevance |
|---------------------|----------|-----------|
| Glutathione (GSH) | Essential cofactor | Substrate for peroxide reduction |
| FSP1/AIFM2 | Parallel ferroptosis suppressor | Redundant protection pathway |
| NRF2 | Transcription factor | Regulates GPX4 expression |
| Ferroportin | Iron exporter | Reduces labile iron pool |
| ACSL4 | Fatty acid metabolism | Generates PUFA-PL substrates |
Key Publications
[Friedmann Angeli et al., Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure (2014)](https://doi.org/10.1038/ncb3064) — Nature Cell Biology. Landmark study establishing GPX4 as the master regulator of ferroptosis.
[Yang et al., Regulation of ferroptotic cancer cell death by GPX4 (2014)](https://doi.org/10.1016/j.cell.2014.03.011) — Cell. Characterization of GPX4's role in ferroptosis regulation.
[Hambright et al., Ablation of the ferroptosis inhibitor glutathione peroxidase-4 in the forebrain accelerates neurodegeneration (2017)](https://doi.org/10.1080/15548627.2016.1277304) — [Autophagy](/entities/autophagy). Demonstrates GPX4's neuroprotective role in vivo.
[Chen et al., ATF4 promotes neuroprotection in ferroptosis by regulating the SLC7A11-GPX4 axis (2023)](https://pubmed.ncbi.nlm.nih.gov/37639723/) — Demonstrates the stress response pathway regulating GPX4 in neurons.
[Stockwell et al., Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease (2017)](https://doi.org/10.1016/j.cell.2017.01.014) — Cell. Comprehensive review of ferroptosis mechanisms.See Also
- [Ferroptosis](/mechanisms/ferroptosis)
- [FSP1/AIFM2](/proteins/fsp1)
- [Ferritin Heavy Chain](/proteins/ferritin-h)
- [NRF2](/proteins/nrf2)
- [Iron Metabolism in Neurodegeneration](/mechanisms/iron-metabolism-neurodegeneration)
- [Glutathione System](/mechanisms/glutathione-system)
References
[Friedmann Angeli JP, et al, Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure (2014)](https://doi.org/10.1038/ncb3064)
[Ingold I, et al, Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis (2018)](https://doi.org/10.1016/j.cell.2017.11.048)
[Scheerer P, et al, Structural basis for catalytic activity of glutathione peroxidase 4 (2007)](https://doi.org/10.1042/BJ20070428)
[Brigelius-Flohé R, Maiorino M, Glutathione peroxidases (2013)](https://doi.org/10.1016/j.bbagen.2012.11.020)
[Stockwell BR, et al, Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease (2017)](https://doi.org/10.1016/j.cell.2017.09.021)
[Hambright WS, et al, Ablation of the ferroptosis inhibitor glutathione peroxidase-4 in forebrain neurons accelerates neurodegeneration (2017)](https://doi.org/10.1080/15548627.2016.1277304)
[Do Van B, et al, Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC (2021)](https://doi.org/10.1016/j.nbd.2021.105610)
[Jiang X, et al, Ferroptosis: mechanisms, biology and role in disease (2021)](https://doi.org/10.1038/s41580-020-00324-8)
[Chen X, et al, Broadening horizons: The role of ferroptosis in cancer (2021)](https://doi.org/10.1038/s41571-020-00462-0)
[Zilka O, et al, On the mechanisms of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death (2017)](https://doi.org/10.1021/acscentsci.7b00028)Pathway Diagram
The following diagram shows key molecular relationships for GPX4 (Glutathione Peroxidase 4) based on knowledge graph edges:
Mermaid diagram (expand to render)
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
- [Senescence-Induced Lipid Peroxidation Spreading](/hypothesis/h-7957bb2a) — <span style="color:#ffd54f;font-weight:600">0.54</span> · Target: GPX4/SLC7A11
Pathway Diagram
The following diagram shows the key molecular relationships involving GPX4 (Glutathione Peroxidase 4) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)