肿瘤缺氧与癌症患者的预后较差有关，并且会降低放射治疗 (RT) 的疗效。本研究探讨二甲双胍增强缺氧癌细胞放射敏感性的潜力。进行了初步实验以验证缺氧对放射反应的影响。在用二甲双胍处理的缺氧、辐射细胞中评估活性氧（ROS）水平、细胞迁移和细胞死亡。采用蛋白质组学和本体论分析来识别与二甲双胍放射增敏作用相关的分子靶标。蛋白质组学和本体论研究结果通过患者样本和体外研究得到了验证。二甲双胍会放大细胞死亡，诱导 DNA 断裂，减少细胞迁移，并提高缺氧、辐射细胞中的 ROS 水平。蛋白质组学分析表明，GAPDH 和 TAGLN2 被确定为与二甲双胍放射增敏作用相关的关键靶标。口腔癌患者的 TAGLN2 水平升高，GAPDH 水平降低。在缺氧、辐射细胞中，二甲双胍下调 TAGLN2 并上调 GAPDH。此外，二甲双胍降低了突变 p53 的水平。这项研究表明，二甲双胍可以通过调节 GAPDH 和 TAGLN2 来增强缺氧细胞的放射敏感性。此外，二甲双胍可有效降低缺氧条件下辐射细胞中突变的 p53 水平。© 2024 John Wiley

Tumor hypoxia is associated with a poorer prognosis in cancer patients and can diminish the efficacy of radiation therapy (RT). This study investigates the potential of metformin to enhance radiosensitivity in hypoxic cancer cells.Preliminary experiments were conducted to validate the impact of hypoxia on radiation response. Reactive oxygen species (ROS) levels, cell migration, and cell death were assessed in hypoxic, radiated cells treated with metformin. Proteomic and ontological analyses were employed to identify molecular targets associated with the radiosensitizing effect of metformin. Proteomic and ontological findings were validated through patient samples and in vitro studies.Metformin amplified cell death, induced DNA fragmentation, decreased cell migration, and elevated ROS levels in hypoxic, radiated cells. Proteomic analyses revealed that GAPDH and TAGLN2 were identified as pivotal targets linked to the radiosensitizing effect of metformin. Oral cancer patients exhibited elevated levels of TAGLN2 and reduced levels of GAPDH. Metformin downregulated TAGLN2 and upregulated GAPDH in hypoxic, radiated cells. Additionally, metformin reduced levels of mutated p53.This study suggests that metformin can enhance radiosensitivity in hypoxic cells, operating through modulation of GAPDH and TAGLN2. Furthermore, metformin effectively reduces mutated p53 levels in radiated cells under hypoxic conditions.© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.