GPX4 (Glutathione Peroxidase 4)

Migration, Crosslink

📖

GPX4 (Glutathione Peroxidase 4)

active

wiki page Created: 2026-04-02T07:19:07 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-gpx4

📖 Wiki Page

protein1014 wordssynced 2026-04-02

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 molecules

The 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 genes

Therapeutic 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.

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)

📖 View canonical wiki page →

Related Entities

GPX4

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-gpx4
kg_node_id	GPX4
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-b4776afbf0da
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-gpx4'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

49

Outgoing

115

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

GPX4 (Glutathione Peroxidase 4)

GPX4 (Glutathione Peroxidase 4)

Overview

GPX4 (Glutathione Peroxidase 4)

Overview

Structure and Domains

Normal Function

Role in Neurodegeneration

Ferroptosis and Neurodegeneration

Molecular Mechanisms

Therapeutic Targeting

GPX4 Activation Strategies

Ferroptosis Inhibitors

System Xc- Modulators

Protein Interactions

Key Publications

See Also

References

Pathway Diagram

Pathway Diagram

💬 Discussion

📗 Cite This Artifact

GPX4 (Glutathione Peroxidase 4)

GPX4 (Glutathione Peroxidase 4)

Overview

GPX4 (Glutathione Peroxidase 4)

Overview

Structure and Domains

Normal Function

Role in Neurodegeneration

Ferroptosis and Neurodegeneration

Molecular Mechanisms

Therapeutic Targeting

GPX4 Activation Strategies

Ferroptosis Inhibitors

System Xc- Modulators

Protein Interactions

Key Publications

See Also

References

Pathway Diagram

Related Hypotheses

Pathway Diagram

💬 Discussion