Abstract
Oral cancer (OC) is one of the most pernicious cancers with increasing incidence and mortality worldwide. Surgery is the primary approach for the treatment of early-stage OC, which reduces the quality of life of the patients. Therefore, there is an urgent need to discover novel treatments for OC. Targeting ferroptosis to induce cell death through the modulation of lipid oxidation has been used as a new approach to treat many cancers. Glutathione (GSH) is a coenzyme factor of GSH peroxidase 4, and it carries potential applicability in treating OC. By using network pharmacology and molecular docking followed by systematic bioinformatic analysis, we aimed to study GSH-targeting ferroptosis to treat OC. We identified 14 core molecular targets, namely, EGFR, PTGS2, HIF1A, VEGFA, TFRC, SLC2A1, CAV1, CDKN2A, SLC3A2, IFNG, NOX4, DDIT4, CA9, and DUSP1, involved in ferroptosis that were targeted by GSH for OC treatment. Functional characterization of these molecular targets showed their importance in the control of cell apoptosis, cell proliferation, and immune responses through various kinase activities such as the mitogen-activated protein kinase activity (e.g., ERK1 and ERK2 cascades) and modulation of TOR signaling (e.g., the HIF-1 signaling pathway). Molecular docking further revealed the direct binding of GSH with EGFR, PTGS2, and HIF1A proteins. These findings provide a novel insight into the targets of GSH in ferroptosis as well as possible molecular mechanisms involved, suggesting the possible use of GSH as a combined therapy for treating OC.
Highlights
Oral cancer (OC) is a type of malignant tumor that occurs in the oral cavity; it includes tongue cancer, gum cancer, palate cancer, oropharyngeal cancer, and lip cancer (Wong and Wiesenfeld 2018)
6639 GSH-associated target genes were identified by searching different databases, and 44 of them were found to be shared with OC- and ferroptosis-associated targets (Figure 1C)
The common targets were subjected to the STRING analysis to FIGURE 2 | components of GSH-targeting ferroptosis genes for treating OC. (C) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed the importance of target genes of GSH action in cell signaling pathways involved in OC
Summary
Oral cancer (OC) is a type of malignant tumor that occurs in the oral cavity; it includes tongue cancer, gum cancer, palate cancer, oropharyngeal cancer, and lip cancer (Wong and Wiesenfeld 2018). Clinical detection of OC may be difficult to achieve because of insidious conditions and anatomical characteristics prior to Glutathione-Anti-Oral Cancer Targeting Ferroptosis initial treatment (Dhanuthai et al, 2018). An in vitro study demonstrated that enhanced intracellular GSH activity induced by natural compounds might have anti-oral cancer action by modulating oxidative stress, autophagy, and cell death (Contant et al, 2021). Network pharmacology-based discovery of individual compounds that act against dysregulated disorders, including malignant cancer (Li et al, 2021a), has been demonstrated (Li et al, 2020). Using a network pharmacology screening approach, our previous study demonstrated the core targets and therapeutic mechanisms of the GSH action against the cleft lip (Li et al, 2021b). Available bioinformatic data of GSH were processed and studied for the potential efficacy against OC via multi-step network pharmacology and molecular docking approach, revealing ferroptosis-associated biotargets and signaling mechanisms
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