Activation of Glutathione Peroxidase 4 as a Novel Anti-inflammatory Strategy
Open accessAbstract
The anti-oxidative enzyme, glutathione peroxidase 4 (GPX4), helps to promote inflammation resolution by eliminating oxidative species produced by the arachidonic acid (AA) metabolic network. Up-regulating its activity has been proposed as a promising strategy for inflammation intervention. In the present study, we aimed to study the effect of GPX4 activator on the AA metabolic network and inflammation related pathways. Using combined computational and experimental screen, we identified a novel compound that can activate the enzyme activity of GPX4 by more than two folds. We further assessed its potential in a series of cellular assays where GPX4 was demonstrated to play a regulatory role. We are able to show that GPX4 activation suppressed inflammatory conditions such as oxidation of AA and NF-κB pathway activation. We further demonstrated that this GPX4 activator can decrease the intracellular ROS level and suppress ferroptosis. Our study suggests that GPX4 activators can be developed as anti-inflammatory or cyto-protective agent in lipid-peroxidation-mediated diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The inactivation of the lipid repair enzyme GPX4 and the induction of ROS, particularly lipid ROS, are the main causes of ferroptosis.
“The inactivation of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the induction of ROS, particularly lipid ROS, are the main causes of iron death. GPX4 has been shown to have a cytoprotective effect by lowering the levels of cellular lipid hydroperoxides.250”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [250]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm0306430 · Cited by 10,057 · see citing works
Regulation of Ferroptotic Cancer Cell Death by GPX4
Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.010 · Cited by 7,713 · see citing works
Halgren, T. A., Murphy, R. B., Friesner, R. A., Beard, H. S., Frye, L. L., Pollard, W. T., & Banks, J. L. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm030644s · Cited by 5,280 · see citing works
Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732 · see citing works
Self-citationCrosstalk of reactive oxygen species and NF-κB signaling
Morgan, M. J., & Liu, Z.-G. (2011) · Cell Research · doi:10.1038/cr.2010.178 · Cited by 3,505 · see citing works
Ferroptosis: Death by Lipid Peroxidation
Yang, W. S., & Stockwell, B. R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.014 · Cited by 3,088 · see citing works
Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis
Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603244113 · Cited by 2,329 · see citing works
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Molina, D. M., Jafari, R., Ignatushchenko, M., Seki, T., Larsson, E. A., Dan, C., Sreekumar, L., Cao, Y., & Nordlund, P. (2013) · Science · doi:10.1126/science.1233606 · Cited by 2,261 · see citing works
Seiler, A., Schneider, M., Förster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Rådmark, O., Wurst, W., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.07.005 · Cited by 1,470 · see citing works
Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., Rosenberg, P. A., Lo, D. C., Weinberg, J. M., Linkermann, A., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja411006a · Cited by 1,146 · see citing works
TNF and ROS crosstalk in inflammation
Blaser, H., Dostert, C., Mak, T. W., & Brenner, D. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.12.002 · Cited by 1,008 · see citing works
The selenoenzyme phospholipid hydroperoxide glutathione peroxidase
Ursini, F., Maiorino, M., & Gregolin, C. (1985) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(85)90182-5 · Cited by 992 · see citing works
Ursini, F., Maiorino, M., Valente, M., Ferri, L., & Gregolin, C. (1982) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(82)90150-3 · Cited by 884 · see citing works
Regulated necrosis: disease relevance and therapeutic opportunities
Conrad, M., Angeli, J. P. F., Vandenabeele, P., & Stockwell, B. R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.6 · Cited by 630 · see citing works
Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology
Buczynski, M. W., Dumlao, D. S., & Dennis, E. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r900004-jlr200 · Cited by 531 · see citing works
Glutathione peroxidases and redox-regulated transcription factors
Brigelius‐Flohé, R. (2006) · Biological Chemistry · doi:10.1515/bc.2006.166 · Cited by 361 · see citing works
Turning enzymes ON with small molecules
Zorn, J. A., & Wells, J. A. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.318 · Cited by 220 · see citing works
Yuan, Y., Pei, J., & Lai, L. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319120019 · Cited by 199 · see citing works
Self-citationLigBuilder 2: A Practical de Novo Drug Design Approach
Yuan, Y., Pei, J., & Lai, L. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci100350u · Cited by 199 · see citing works
Self-citationSchnurr, K., Belkner, J., Ursini, F., SCHEWE, T., & Kühn, H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.9.4653 · Cited by 198 · see citing works
Selenoenzymes regulate the activity of leukocyte 5-lipoxygenase via the peroxide tone.
Weitzel, F., & Wendel, A. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53251-8 · Cited by 194 · see citing works
Finding multiple target optimal intervention in disease‐related molecular network
Yang, K., Bai, H., Ouyang, Q., Lai, L., & Tang, C. (2008) · Molecular Systems Biology · doi:10.1038/msb.2008.60 · Cited by 186 · see citing works
Self-citationScheerer, P., Borchert, A., Krauß, N., Wessner, H., Gerth, C., Höhne, W. E., & Kühn, H. (2007) · Biochemistry · doi:10.1021/bi700840d · Cited by 179 · see citing works
Roveri, A., Maiorino, M., & Ursini, F. (1994) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(94)33023-9 · Cited by 169 · see citing works
Imai, H., Narashima, K., Arai, M., Sakamoto, H., Chiba, N., & Nakagawa, Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.4.1990 · Cited by 169 · see citing works
Novel Allosteric Activators for Ferroptosis Regulator Glutathione Peroxidase 4
Li, C., Deng, X., Zhang, W., Xie, X., Conrad, M., Liu, Y., Angeli, J. P. F., & Lai, L. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00315 · Cited by 153 · see citing works
Self-citationNovel Ferroptosis Inhibitors with Improved Potency and ADME Properties
Hofmans, S., Berghe, T. V., Devisscher, L., Hassannia, B., Lyssens, S., Joossens, J., der Veken, P. V., Vandenabeele, P., & Augustyns, K. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01641 · Cited by 142 · see citing works
Dynamic Simulations on the Arachidonic Acid Metabolic Network
Yang, K., Ma, W., Liang, H., Ouyang, Q., Tang, C., & Lai, L. (2007) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0030055 · Cited by 115 · see citing works
Self-citationSattler, W., Maiorino, M., & Stocker, R. (1994) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1994.1105 · Cited by 107 · see citing works
Molecular determinants of Hv1 proton channel inhibition by guanidine derivatives
Hong, L., Kim, I. H., & Tombola, F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1324012111 · Cited by 99 · see citing works
Maiorino, M., Thomas, J. P., Girotti, A. W., & Ursini, F. (1991) · Free Radical Research Communications · doi:10.3109/10715769109145777 · Cited by 94 · see citing works
Blocking tumor cell eicosanoid synthesis by GPx4 impedes tumor growth and malignancy
Heirman, I., Ginneberge, D., Brigelius‐Flohé, R., Hendrickx, N., Agostinis, P., Brouckaert, P., Rottiers, P., & Grooten, J. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.08.033 · Cited by 87 · see citing works
Motions of Allosteric and Orthosteric Ligand-Binding Sites in Proteins are Highly Correlated
Ma, X., Meng, H., & Lai, L. (2016) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6b00039 · Cited by 81 · see citing works
Self-citationDiverse Ways of Perturbing the Human Arachidonic Acid Metabolic Network To Control Inflammation
Meng, H., Liu, Y., & Lai, L. (2015) · Accounts of Chemical Research · doi:10.1021/acs.accounts.5b00226 · Cited by 76 · see citing works
Self-citationHatzelmann, A., & Ullrich, V. (1987) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1987.tb13595.x · Cited by 75 · see citing works
Systems Biology Brings New Dimensions for Structure-Based Drug Design
Pei, J., Yin, N., Ma, X., & Lai, L. (2014) · Journal of the American Chemical Society · doi:10.1021/ja504810z · Cited by 74 · see citing works
Self-citationHatzelmann, A., SCHATZ, M., & Ullrich, V. (1989) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1989.tb14678.x · Cited by 72 · see citing works
Development of a fluorescence-based enzyme assay of human 5-lipoxygenase
Pufahl, R. A., Kasten, T. P., Hills, R., Gierse, J. K., Reitz, B. A., Weinberg, R. A., & Masferrer, J. L. (2007) · Analytical Biochemistry · doi:10.1016/j.ab.2007.02.009 · Cited by 63 · see citing works
Bao, Y., Jemth, P., Mannervik, B., & Williamson, G. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00591-7 · Cited by 62 · see citing works
Sutherland, M., Shankaranarayanan, P., SCHEWE, T., & Nigam, S. (2000) · Biochemical Journal · doi:10.1042/bj3530091 · Cited by 55 · see citing works
Dynamic Modeling of Human 5-Lipoxygenase–Inhibitor Interactions Helps To Discover Novel Inhibitors
Wu, Y., He, C., Gao, Y., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201497k · Cited by 55 · see citing works
Meng, H., McClendon, C. L., Dai, Z., Li, K., Zhang, X., He, S., Shang, E., Liu, Y., & Lai, L. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01011 · Cited by 50 · see citing works
Self-citationChen, C.-J., Huang, H., & Chang, W.-C. (2003) · The FASEB Journal · doi:10.1096/fj.02-0847fje · Cited by 43 · see citing works
Discovery of Dual Target Inhibitors against Cyclooxygenases and Leukotriene A4Hydrolyase
Chen, Z., Wu, Y., Liu, Y., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200063s · Cited by 42 · see citing works
Self-citationHuang, H.-S., Chen, C.-J., Lu, H. S., & Chang, W. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00130-6 · Cited by 35 · see citing works
He, S., Li, C., Liu, Y., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301900x · Cited by 33 · see citing works
Self-citationJiang, X., Zhou, L., Wei, D., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.10.044 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ferroptosis: past, present and future
Li, J., Cao, F., Yin, H.-L., Huang, Z.-J., Lin, Z.-T., Mao, N., Sun, B., & Wang, G. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-2298-2 · Cited by 4,171 · see citing works
Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443 · see citing works
“GPX4 has been shown to have a cytoprotective effect by lowering the levels of cellular lipid hydroperoxides.(250) Several pro-inflammatory cytokines, including TNF, PGE2, IL-1, and IL-6, have been demonstrated to exert a direct influence on the levels and function of GPX4 within cancer cells;(251) for example, TNF tre…”
BackgroundSelf-citationRole of Glutathione in Cancer: From Mechanisms to Therapies
Kennedy, L., Sandhu, J. K., Harper, M.-E., & Cuperlovic-Culf, M. (2020) · Biomolecules · doi:10.3390/biom10101429 · Cited by 880 · see citing works
The emerging role of ferroptosis in inflammation
Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., Xu, S., Gao, Y., Chen, X., Sui, X., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110108 · Cited by 739 · see citing works
Qi, J., Kim, J.-W., Zhou, Z., Lim, C.-W., & Kim, B. (2020) · The American Journal of Pathology · doi:10.1016/j.ajpath.2019.09.011 · Cited by 338 · see citing works
- Authors
- Li, C., Deng, X., Xie, X., Liu, Y., Friedmann Angeli, J. P., & Lai, L.
- Affiliations
- Peking University (CN)
- Corresponding author
- Lai, Luhua
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2018-10-03
- Volume
- 9
- Pages
- 1120-1120
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC6178849
- OpenAlex
- W2891074355
- Cited by
- 183
- References
- 48
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 40 · 2023: 34 · 2022: 29 · 2021: 17 · 2020: 13 · 2019: 9
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Funders
- Ministry of Science and Technology of the People’s Republic of China (2016YFA0502303, 2015CB910300)
- National Natural Science Foundation of China (21633001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- GPX4, anti-inflammatory strategies, arachidonic acid metabolism, lipid peroxidation, NF-κB signaling, reactive oxygen species, ferroptosis, oxidative stress, inflammation resolution, cytoprotection
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
