Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer.
Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer.
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DOI：
10.3389/fphar.2022.851540
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发表时间：
2022
影响因子：
5.6
通讯作者：
Zhan L
中科院分区：
文献类型：
--
作者：
Huang C;Zhan L
口腔癌（oral cancer，OC）是世界范围内发病率和死亡率不断上升的恶性肿瘤之一。手术是治疗早期OC的主要方法，这降低了患者的生活质量。因此，迫切需要发现新的治疗OC的方法。靶向铁凋亡通过调节脂质氧化诱导细胞死亡已被用作治疗许多癌症的新方法。谷胱甘肽（GSH）是GSH过氧化物酶4的辅酶因子，在治疗OC中具有潜在的应用价值。通过网络药理学和分子对接，结合系统的生物信息学分析，我们旨在研究以GSH为靶点的铁凋亡治疗OC。我们确定了14个核心分子靶点，即EGFR、PTGS 2、HIF 1A、VEGFA、TFRC、SLC 2A 1、CAV 1、CDKN 2A、SLC 3A 2、IFNG、NOX 4、DDIT 4、CA 9和DUSP 1，这些靶点参与GSH用于OC治疗的铁凋亡。这些分子靶标的功能表征显示了它们在通过各种激酶活性控制细胞凋亡、细胞增殖和免疫应答中的重要性，所述激酶活性例如促分裂原活化蛋白激酶活性（例如，ERK 1和ERK 2级联）和TOR信号传导的调节（例如，HIF-1信号通路）。分子对接进一步揭示了GSH与EGFR、PTGS 2和HIF 1A蛋白的直接结合。这些研究结果提供了一个新的见解谷胱甘肽在铁凋亡的目标，以及可能的分子机制参与，这表明可能使用的GSH作为治疗OC的联合治疗。
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.
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