| Gene | GPX4 |
| UniProt | P36969 |
| Molecular Weight | 22 kDa |
| Subcellular Localization | Cytosol, Mitochondria, Nucleus |
| PDB Structures | 5L71, 2OBI |
| Aliases | Phospholipid Hydroperoxide Glutathione Peroxidase, PHGPx |
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—a regulated cell death pathway driven by iron-dependent lipid peroxidation.[1]
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.[2]
Key structural features:
The crystal structure reveals a compact globular protein with the selenocysteine positioned in a surface-accessible pocket that accommodates phospholipid substrates.[3]
GPX4 serves as the primary defense against lipid peroxidation in cellular membranes:[4]
The catalytic cycle involves:
GPX4-SeH + LOOH → GPX4-SeOH + LOH
GPX4-SeOH + GSH → GPX4-SeSG + H2O
GPX4-SeSG + GSH → GPX4-SeH + GSSG
GPX4 dysfunction is increasingly recognized as central to neurodegenerative diseases through ferroptosis:[5]
Amyotrophic Lateral Sclerosis:
Multiple Sclerosis:
The ferroptosis pathway involves several key players that intersect with GPX4:[8]
Several approaches are being explored to enhance GPX4 function:[9]
| 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 |
Indirect approaches to support GPX4 function:[10]
| 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 |
Friedmann Angeli et al., Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure (2014) — 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) — 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) — Autophagy. Demonstrates GPX4's neuroprotective role in vivo.
Chen et al., ATF4 promotes neuroprotection in ferroptosis by regulating the SLC7A11-GPX4 axis (2023) — 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) — Cell. Comprehensive review of ferroptosis mechanisms.
Friedmann Angeli JP, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure. Nature Cell Biology. 2014. ↩︎
Ingold I, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell. 2018. ↩︎
Scheerer P, et al. Structural basis for catalytic activity of glutathione peroxidase 4. Biochemical Journal. 2007. ↩︎
Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochimica et Biophysica Acta. 2013. ↩︎
Stockwell BR, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017. ↩︎
Hambright WS, et al. Ablation of the ferroptosis inhibitor glutathione peroxidase-4 in forebrain neurons accelerates neurodegeneration. Autophagy. 2017. ↩︎
Do Van B, et al. Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiology of Disease. 2021. ↩︎
Jiang X, et al. Ferroptosis: mechanisms, biology and role in disease. Nature Reviews Molecular Cell Biology. 2021. ↩︎
Chen X, et al. Broadening horizons: The role of ferroptosis in cancer. Nature Reviews Clinical Oncology. 2021. ↩︎
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. ACS Central Science. 2017. ↩︎