Huang Chen, Zhan Lei
The Center for Data Science in Health and Medicine, Business School, Qingdao University, Qingdao, China.
Department of Ophthalmology, The Second People's Hospital of Guilin, Guilin, China.
Front Pharmacol. 2022 Mar 14;13:851540. doi: 10.3389/fphar.2022.851540. eCollection 2022.
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.
口腔癌（OC）是全球发病率和死亡率不断上升的最恶性癌症之一。手术是治疗早期OC的主要方法，但会降低患者的生活质量。因此，迫切需要发现针对OC的新治疗方法。通过调节脂质氧化靶向铁死亡以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）是谷胱甘肽过氧化物酶4的辅酶因子，在治疗OC方面具有潜在的适用性。通过网络药理学和分子对接，随后进行系统的生物信息学分析，我们旨在研究靶向GSH的铁死亡治疗OC。我们确定了14个核心分子靶点，即表皮生长因子受体（EGFR）、前列腺素内过氧化物合酶2（PTGS2）、缺氧诱导因子1α（HIF1A）、血管内皮生长因子A（VEGFA）、转铁蛋白受体（TFRC）、溶质载体家族2成员1（SLC2A1）、窖蛋白1（CAV1）、细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）、溶质载体家族3成员2（SLC3A2）、干扰素γ（IFNG）、烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）、DNA损伤诱导转录本4（DDIT4）、碳酸酐酶9（CA9）和双特异性磷酸酶1（DUSP1），它们参与铁死亡，是GSH治疗OC的靶点。这些分子靶点的功能表征表明，它们通过各种激酶活性，如丝裂原活化蛋白激酶活性（如细胞外信号调节激酶1和2级联反应）和雷帕霉素靶蛋白信号传导调节（如HIF-1信号通路），在控制细胞凋亡、细胞增殖和免疫反应中具有重要作用。分子对接进一步揭示了GSH与EGFR、PTGS2和HIF1A蛋白的直接结合。这些发现为GSH在铁死亡中的靶点以及可能涉及的分子机制提供了新的见解，表明GSH可能作为治疗OC的联合疗法。
