他莫昔芬（TAM）耐药性仍然是晚期乳腺癌（BCa）治疗的主要障碍。除了竞争性抑制雌激素受体 (ER) 信号通路外，通过增加活性氧 (ROS) 来抑制线粒体功能对于增强 TAM 药效至关重要。在这里，我们发现 RelB 通过抑制 TAM 引起的铁死亡来促进 TAM 抵抗。 TAM 诱导的 ROS 水平促进 TAM 敏感细胞中的铁死亡，但在具有高 RelB 水平的 TAM 抗性细胞中，这种影响减轻。从机制上讲，RelB 通过转录上调谷胱甘肽过氧化物酶 4 (GPX4) 抑制铁死亡。因此，提高敏感细胞中的 RelB 和 GPX4 会增加 TAM 耐药性，相反，降低耐药细胞中的 RelB 和 GPX4 会降低 TAM 耐药性。此外，抑制 RelB 转录激活可通过增强体外和体内铁死亡来使 TAM 耐药细胞重新敏感。 TAM 抗性细胞中 GPX4 的失活通过增加铁死亡介导的细胞死亡而持续使 TAM 重新敏感。总之，这项研究发现，抑制铁死亡可通过 RelB 上调的 GPX4 促进 BCa 的 TAM 抗性。版权所有 © 2023 作者。由 Elsevier B.V. 出版。保留所有权利。

Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo. The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.