Abstract
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.
Highlights
Glutathione peroxidase 4 (GPX4; E.C.: 1.11.1.12), called phospholipid hydroperoxide glutathione peroxidase (PHGPx), is a selenium-dependent glutathione peroxidase (GPx; Ursini et al, 1982)
We aimed to study the effect of GPX4 activator on the arachidonic acid (AA) metabolic network and inflammation related pathways
We further demonstrated that compound 102 can increase the Tm of hGPX4-C by about 2◦C (Supplementary Figure S1), supporting for specific binding
Summary
Glutathione peroxidase 4 (GPX4; E.C.: 1.11.1.12), called phospholipid hydroperoxide glutathione peroxidase (PHGPx), is a selenium-dependent glutathione peroxidase (GPx; Ursini et al, 1982). As a member of the GPxs family, GPX4 can catalyze the reduction of peroxides at the expense of glutathione. Lipid hydroperoxides have been implicated in a variety of pathophysiological processes, including inflammation, atherogenesis, neurodegeneration, and aging. Besides being the sole antioxidant enzyme able to repair lipid peroxides, GPX4 is a moonlighting protein that regulate eicosanoid biosynthesis (Weitzel and Wendel, 1993; Schnurr et al, 1996; Huang et al, 1998; Imai et al, 1998) and cytokine signaling (Brigelius-Flohé, 2006).
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