最近的研究强调了铁死亡在治疗乳腺癌方面的潜力。然而，铁死亡诱导在最常见的亚型雌激素受体阳性（ER  ）乳腺癌中的功效仍未得到充分研究。这项研究揭示了内质网靶向内分泌药物的短期和长期治疗都会使内质网乳腺癌细胞对铁死亡诱导剂，特别是 GPX4 抑制剂敏感，揭示了一种非突变致敏机制。基于这一发现，我们引入了专门用于评估乳腺癌铁死亡易感性的 55 基因特征评分 (FERscore)。来自细胞系和原发性肿瘤的数据表明，与其他亚型相比，ER 乳腺癌的 FER 分数显着降低；然而，内分泌耐药性 ER 肿瘤细胞和内分泌治疗后残留肿瘤的 FERscore 显着增加。此外，FERscore 与间充质性状、干性、免疫细胞浸润和癌症相关成纤维细胞富集呈正相关，而与雌激素反应性和 DNA 修复能力呈负相关。此外，FERscore 被证明可以有效预测乳腺癌抗 ER、抗 HER2、聚（ADP-核糖）聚合酶抑制剂和抗血管生成疗法的治疗反应。总之，铁死亡诱导成为乳腺癌治疗的一个有前途的途径。 FERscore 提供了一种创新工具，用于识别可能受益于铁死亡诱导疗法的患者，尤其是那些对 GPX4 抑制剂有反应的患者。© 2024。作者。

Recent studies have highlighted the potential of ferroptosis in treating breast cancer. However, the efficacy of ferroptosis induction in the most common subtype, estrogen receptor-positive (ER + ) breast cancer, remains inadequately explored. This study unveils that both short-term and long-term treatment with ER-targeted endocrine agents sensitizes ER+ breast cancer cells to ferroptosis inducers, particularly the GPX4 inhibitor, revealing a non-mutational sensitization mechanism. Based on this finding, we introduce a 55-gene signature score (FERscore) tailored to assess ferroptosis susceptibility in breast cancer. Data from cell lines and primary tumors demonstrate significant lower FERscores in ER+ breast cancer compared to other subtypes; however, FERscores dramatically increase in endocrine-resistant ER+ tumor cells and residual tumors post-endocrine therapy. Furthermore, FERscore correlates positively with mesenchymal traits, stemness, immune cell infiltration, and cancer-associated fibroblasts enrichment, while inversely correlating with estrogen responsiveness and DNA repair capacity. Additionally, the FERscore proves effective in predicting therapeutic responses to anti-ER, anti-HER2, poly (ADP-ribose) polymerase inhibitor, and anti-angiogenesis therapies in breast cancer. In summary, ferroptosis induction emerges as a promising avenue in breast cancer therapy. The FERscore offers an innovative tool for identifying patients who may benefit from ferroptosis-inducing therapies, especially those responsive to GPX4 inhibitors.© 2024. The Author(s).