Eya3介导的铁死亡耐受在宫颈癌放疗抵抗中的作用和机制研究

放疗抵抗是导致宫颈癌患者复发转移的重要原因，但尚无有效的药物应用于临床，相关机制和治疗靶点是目前的研究难点。申请者前期对病人样本进行蛋白组学分析发现，放疗抵抗组织呈现铁死亡耐受的特征，且初步证实眼缺失同源物Eya3的高表达是宫颈癌铁死亡耐受产生的关键。结合初步的机制研究推测：放疗抵抗组织中过表达的Eya3通过与AKT竞争结合蛋白磷酸酶PHLPP，导致AKT持续激活并通过下游分子SCD1和SREBP1抑制细胞内脂质过氧化物的累积，最终造成了铁死亡耐受的产生。铁死亡在宫颈癌放疗抵抗中的作用尚无研究报道。本课题拟从一个新的视角出发，在临床样本检测的基础上，综合利用多种实验手段，揭示铁死亡在宫颈癌放疗抵抗中的作用，并探索Eya3/PHLPP-AKT信号轴调控铁死亡耐受的分子机制，以期为解除铁死亡抑制并治疗宫颈癌放疗抵抗提供新的策略和依据。

Radioresistance is an important reason for recurrence and metastasis of cervical cancer patients, but there is no effective drug for clinical use. The related mechanisms and treatment targets are the current research difficulties. The preliminary study of the patients showed that the radioresistant tissues showed the characteristics of ferroptotic tolerance, and the high expression of Eye absence homologue Eya3 was the key to the production of ferroptotic tolerance in cervical cancer. Combined with the preliminary mechanism exploration, the overexpression of Eya3 can bind with protein phosphatase PHLPP by competing with AKT, causing continuously AKT activation and thus inhibited accumulation of peroxides via downstream molecules SCD1 and SREBP1, which eventually leads to the production of ferroptotic tolerance. The role of ferroptosis in the radioresistant cervical cancer remains unclear. This project aims to explore the role of ferroptosis in radioresistant cervical cancer and investigate the molecular mechanism of Eya3/PHLPP-AKT signaling axis in ferroptotic tolerance, in order to provide new strategies and basis for relieving the ferroptotic suppression and treating the radioresistant cervical cancer based on clinical sample detection and comprehensive utilization of various experimental methods.