Unraveling the Dual Nature of GPx4: From Ferroptosis Regulation to Therapeutic Innovation in Human Pathologies
Main Article Content
Abstract
GPx4 (Glutathione peroxidase 4) is a Sec (selenocysteine)-dependent monomeric antioxidant enzyme capable of maintaining cellular redox homeostasis by catalyzing the reduction of lipid peroxides by GSH (glutathione). As a core regulatory node of the ferroptosis pathway, GPx4 not only directly affects apoptosis, but also deeply participates in tumorigenesis, cellular senescence, and other key biological processes by inhibiting the lipid peroxidation cascade; at the same time, GPx4 also exhibits a key targeting value in neurodegenerative diseases, metabolic disorders, and cardiovascular pathologies.The aim of this paper is to analyze the protein structure and biological function of GPx4, to systematically explore the core regulatory role of this enzyme in the ferroptosis pathway and its molecular mechanism in various diseases, and ultimately to break through the existing therapeutic bottlenecks based on the current progress of research, and to provide a new idea for the precise intervention strategy targeting GPx4.
Keywords:
GPx4, Ferroptosis, Disease
Article Details
How to Cite
WU, Chunxia et al.
Unraveling the Dual Nature of GPx4: From Ferroptosis Regulation to Therapeutic Innovation in Human Pathologies.
Medical Research Archives, [S.l.], v. 13, n. 8, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6801>. Date accessed: 17 nov. 2025.
doi: https://doi.org/10.18103/mra.v13i8.6801.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C. Purification from Pig Liver of a Protein Which Protects Liposomes and Biomembranes from Peroxidative Degradation and Exhibits Glutathione Peroxidase Activity on Phosphatidylcholine Hydroperoxides. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1982;710:197-211
4. Pei J, Pan X, Wei G, Hua Y. Research Progress of Glutathione Peroxidase Family (GPX) in Redoxidation. Front Pharmacol. 2023;14
5. Brigelius-Flohé R, Kipp AP. Physiological functions of GPx2 and its role in inflammation-triggered carcinogenesis. ENVIRONMENTAL STRESSORS IN BIOLOGY AND MEDICINE. 2012;1259:19-25
6. Nirgude S, Choudhary B. Insights into the role of GPX3, a highly efficient plasma antioxidant, in cancer. Biochem Pharmacol. 2021;184
7. Brigelius-Flohe R. Glutathione Peroxidases and Redox-Regulated Transcription Factors. Oxidative Stress and Signal Transduction. 1997:415-440
8. Zhang W, Liu Y, Liao Y, Zhu C, Zou Z. GPX4, ferroptosis, and diseases. Biomed Pharmacother. 2024;174:116512
9. Kelner MJ, Montoya MA. Structural Organization of the Human Selenium-Dependent Phospholipid Hydroperoxide Glutathione Peroxidase Gene (gpx4): Chromosomal Localization to 19P13.3. Biochem Biophys Res Commun. 1998;249:53-55
10. Knopp EA, Arndt TL, Eng KL et al. Murine Phospholipid Hydroperoxide Glutathione Peroxidase: Cdna Sequence, Tissue Expression, and Mapping. Mamm Genome. 1999;10:601-605
11. Scheerer P, Borchert A, Krauss N et al. Structural Basis for Catalytic Activity and Enzyme Polymerization of Phospholipid Hydroperoxide Glutathione Peroxidase-4 (Gpx4). Biochemistry. 2007;46 31:9041-9
12. Roveri A, Maiorino M, Nisii C, UrsinI F. Purification and Characterization of Phospholipid Hydroperoxide Glutathione Peroxidase from Rat Testis Mitochondrial Membranes. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1994;1208:211-221
13. Sok SPM, Pipkin K, Van Remmen H, Fan Z, Zhao M. Gpx4 Regulates Invariant NKT Cell Homeostasis and Function by Preventing Lipid Peroxidation and Ferroptosis. J Immunol. 2024;212
14. Li Z, Zhu Z, Liu Y, Liu Y, Zhao H. Function and Regulation of GPX4 in the Development and Progression of Fibrotic Disease. J Cell Physiol. 2022;237:2808-2824
15. Pillai R, Uyehara-Lock JH, Bellinger FP. Selenium and selenoprotein function in brain disorders. IUBMB Life. 2014;66:229-239
16. Miao Y, Chen Y, Xue F et al. Contribution of Ferroptosis and GPX4’s Dual Functions to Osteoarthritis Progression. EBioMedicine. 2022;76:103847-103847
17. Seibt TM, Proneth B, Conrad M. Role of GPX4 in Ferroptosis and Its Pharmacological Implication. Free radical biology & medicine. 2018;133:144-152
18. Forcina GC, Dixon SJ. GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis. Proteomics. 2019;19.0:e1800311
19. Imai H, Nakagawa Y. Biological Significance of Phospholipid Hydroperoxide Glutathione Peroxidase (phgpx, GPx4) in Mammalian Cells. Free Radic Biol Med. 2003;34
20. Brigelius-Flohe R. Tissue-Specific Functions of Individual Glutathione Peroxidases. Free Radic Biol Med. 1999;27
21. Xie Y, Kang R, Klionsky DJ, Tang D. GPX4 in Cell Death, Autophagy, and Disease. Autophagy. 2023;19:2621-2638
22. Arai M, Imai H, Sumi D et al. Import into Mitochondria of Phospholipid Hydroperoxide Glutathione Peroxidase Requires A Leader Sequence. Biochem Biophys Res Commun. 1996;227
23. Nomura K, Imai H, Koumura T, Kobayashi T, Nakagawa Y. Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase Inhibits the Release of Cytochrome C from Mitochondria by Suppressing the Peroxidation of Cardiolipin in Hypoglycaemia-Induced Apoptosis. Biochem J. 2000;351:183-193
24. Arai M, Imai H, Koumura T et al. Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. J Biol Chem. 1999;274(8):4924-33
25. Ursini F, Heim S, Kiess M et al. Dual Function of the Selenoprotein PHGPx During Sperm Maturation. Science. 1999;285:1393-1396
26. Liu Y, Wan Y, Jiang Y, Zhang L, Cheng W. GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 2023;1878
27. Conrad M, Moreno SG, Sinowatz F et al. The Nuclear Form of Phospholipid Hydroperoxide Glutathione Peroxidase is a Protein Thiol Peroxidase Contributing to Sperm Chromatin Stability. Mol Cell Biol. 2005;25:7637-7644
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