放射治疗和化疗作为目前癌症主要治疗手段，通过抑制DNA损伤应答（DDR）调控肿瘤对放化疗的敏感性，可望提高肿瘤放化疗疗效。脂类代谢异常是肿瘤代谢的重要组成部分，但通过脂质从头合成途径调控DDR改善其治疗效果尚未见报导。人源性糖蛋白78（glycoprotein 78，gp78）作为几个脂质合成关键蛋白的E3泛素连接酶，维持着细胞脂质稳态。我们前期结果发现gp78降表达和抑制脂质从头合成均会促进肿瘤细胞DDR，抑制其放疗敏感性。本项目假设：gp78通过脂质从头合成通路调控DDR及肿瘤细胞的放射敏感性。为了证明该研究假设，我们拟从细胞、荷瘤鼠水平探究gp78-Insig-SREBP通路以及小分子脂质调控DDR的分子机制。其意义在于为靶向脂质代谢增加肿瘤患者的放化疗敏感性提供靶标以及理论依据。

Radiotherapy and chemotherapy are the major treatment methods for cancer. To improve the radiotherapy effect and increase the radiosensitivity of the tumor tissue through the DNA damage response(DDR)remains to be solved. Metabolic reprogramming occurs in tumor cells, human glycoprotein 78 (gp78) is the E3 ubiquitin ligase of several key lipid synthesis proteins, which maintains cell lipid homeostasis. Our recent findings demonstrate that knockdown gp78 and inhibition of lipid de novo synthesis promote DDR and inhibit the radiosensitivity of tumor cells. Our preliminary data indicate that gp78 regulates the DDR and radiosensitivity of tumor cells through lipid biosynthesis pathway. The proposed study will determine physiological mechanisms of gp78-Insig-SREBP signaling in the DDR, and provide potential strategies for targeting lipid metabolism to increase radiosensitivity.