他莫昔芬耐药严重影响乳腺癌患者预后，阐明其机制具有重要临床意义。我们已发表的研究提示提示KLF4能够逆转他莫昔芬耐药，但具体机制不明。铁死亡是近年才发现的一种新的程序性细胞坏死形式，已被证实与许多病理生理过程有关，更有望成为肿瘤治疗的新靶点。本项目的前期研究发现他莫昔芬耐药细胞铁死亡水平显著下降，而KLF4可促进他莫昔芬耐药细胞铁死亡。此外，我们还发现KLF4与铁死亡关键蛋白SLC7A11结合而促进SLC7A11降解，但调控机制不明。本项目拟通过细胞实验、生信分析、动物实验、临床样本和类器官模型探索分析:(1)铁死亡影响乳腺癌他莫昔芬耐药;(2)KLF4/SLC7A11信号通路调控他莫昔芬耐药;(3) 阐明KLF4与SLC7A11相互作用的分子机制。旨在揭示KLF4介导的铁死亡在乳腺癌他莫昔芬耐药的机制，并为乳腺癌他莫昔芬耐药的临床诊治、预后判断及药物筛选提供依据。

Tamoxifen resistance is daunting in breast cancer patients, revealing the specific molecular mechanism is guaranteed. Our published study demonstrated that KLF4 re-sensitizes Tamoxifen resistance. Ferroptosis is a newly discovered type of cell death that differs from traditional apoptosis, necrosis, and autophagy. Targeting ferroptosis has been proved to be a promising anti-cancer strategy. Our primary data revealed that ferroptosis is relatively low in Tamoxifen-resistant breast cancer cells, while KLF4 can promote the ferroptosis of Tamoxifen-resistant breast cancer cell. Besides, we also found that KLF4 downregulates SLC7A11, which one of the most critical molecules of ferroptosis, via direct interaction, but the specific molecular mechanism is still unknown. Breast cancer cell lines, bioinformatic analysis, animal model, clinical samples and patient-derived organoid will be utilized: (1)to investigate whether ferroptosis is involved in Tamoxifen resistance;(2)to explore whether KLF4/SLC7A11 pathway is involved in Tamoxifen resistance; (3)to reveal and validate the potential molecular mechanism underneath the interaction between KLF4 and SLC7A11. Our study aims to explore the role and mechanism of KLF4 mediated ferroptosis in Tamoxifen resistance and to provide the novel biomarkers for predicting and intervention of Tamoxifen resistance.