WTX通过调控TRIM21-HMOX1信号轴诱导胃癌细胞铁死亡发挥化疗增敏效应的机制研究

化疗耐药是制约晚期胃癌患者预后的关键因素，目前其调控机制尚未完全阐明。我们前期研究发现抑癌基因WTX可正向调控胃癌细胞铁死亡，且其表达与化疗敏感性显著正相关，进一步筛选出WTX功能相关的结合蛋白TRIM21并证实WTX调控铁死亡关键基因HMOX1表达，结合文献报道，我们推测WTX蛋白可能通过其功能结构域与TRIM21结合，抑制转录因子NRF2入核，导致HMOX1表达下调，诱发细胞铁死亡，从而提高化疗药物的敏感性。本研究拟利用细胞、裸鼠原位模型及WTX基因敲除小鼠模型，深入探讨WTX/TRIM21/NRF2/HMOX1轴的相互作用关系及其在调控胃癌铁死亡和化疗耐药过程中的作用机理，探讨上述信号轴作为联合治疗靶点和化疗疗效监测指标的可行性。该项目的完成，将为寻找能够预测患者化疗敏感性的分子标志物、研发新型铁死亡相关药物以克服胃癌化疗耐药提供新的策略及思路。

Chemoresistance is a key factor restricting the prognosis of patients with advanced gastric cancer,and its regulatory mechanism has not yet been fully elucidated. Our previous study found that the tumor suppressor gene WTX can positively regulate the ferroptosis of gastric cancer cells, and its expression is significantly positively correlated with chemotherapy sensitivity. We further screened the binding protein TRIM21 related to WTX function and confirmed that WTX regulates the expression of HMOX1 which is the key gene in ferroptosis.According to reports in the literature,we speculate that WTX protein may bind to TRIM21 through its functional domain to inhibit the transcription factor NRF2 from shuttling into the nuclear, leading to down-regulation of HMOX1 expression and ferroptosis, thereby increasing the sensitivity of chemotherapeutic drugs. This study intends to use gastric cells, nude mice in situ models and WTX gene knockout mouse models to deeply explore the interaction between WTX/TRIM21/NRF2/HMOX1 axis and its mechanism of regulating ferroptosis and chemotherapy resistance in gastric cancer.To explore the feasibility of the above-mentioned signal axis as a combination therapy target and an indicator for monitoring the efficacy of chemotherapy. The completion of this project will provide new strategies and ideas for finding molecular markers that can predict the sensitivity of patients to chemotherapy and developing new ferroptosis-related drugs to overcome chemotherapy resistance in gastric cancer.