Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer

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.

Identification of potential ferroptosis-related biomarkers and a pharmacological compound in diabetic retinopathy based on machine learning and molecular docking

“…The 2D chemical structure of GSH was downloaded from PubChem. Various databases were utilized to identify whether the FRHGs were potential targets of GSH, as previously described ( 25 ). Molecular docking was utilized to simulate intermolecular binding patterns between GSH and the target proteins.…”

Myricetin Induces Ferroptosis and Inhibits Gastric Cancer Progression by Targeting NOX4

“…NOX enzymes serve as the primary source of ROS within cells and have gained recognition as secondary messengers in diverse signaling pathways . Numerous studies have substantiated that NOX4 is a regulator in the development and metastasis of human cancers. − Moreover, NOX4 is proposed as a hallmark of ferroptosis in tumor cells. − Specifically, a novobiocin derivative, XN4, could induce ferroptosis in GC cells by enhancing NOX4 expression . In the study, NOX4 was identified as a target protein for myricetin, which effectively enhanced the expression and stability of the NOX4 protein.…”

Comprehensive transcriptomic and metabolomic analyses reveal the link between ferroptosis and gut microbiota in CRC

“…Zhu et al combined bioinformatics and immunohistochemical analysis to con rm that CA9 is highly expressed in tongue cancer tissues, but not in adjacent tissues [36], which is promising as an effective marker for the early diagnosis of tongue cancer. A network pharmacology analysis showed that GSH could regulate the ferroptosis pathway by targeting 15 core targets including CA9 to achieve the purpose of treating oral cancer [37]. However, the roles of the above 15 hub genes in CRC have not been reported yet.…”