铁死，一种程序化细胞死亡形式，可以通过xCT转运蛋白（erastin）或GPX4（RSL3）的抑制剂来促进。我们发现，GPX4但不是xCT转运蛋白，在乳腺癌的乳腺腔内选择性上升。与此观察一致的是，大多数乳腺癌细胞系对RSL3非常敏感，对erastin的敏感性有限。在RSL3耐药但不敏感的乳腺癌细胞系中，RSL3诱导HER2途径激活。包括neratinib在内的不可逆HER2抑制剂逆转了在结构耐药的细胞系中的RSL3耐药性。RSL3和neratinib的联合治疗通过线粒体铁依赖的活性氧自由基产生和脂质过氧化增加了铁死。RSL3还激活了复制应激和同时的S期和G2/M期阻滞，导致对目标DNA损伤检查点敏感。综上所述，我们的数据支持在临床试验中探索RSL3与不可逆HER2抑制剂的联合应用。© 2023. The Author(s).

Ferroptosis, a form of programed cell death, can be promoted by inhibitors of the xCT transporter (erastin) or GPX4 (RSL3). We found that GPX4, but not the xCT transporter, is selectively elevated in luminal breast cancer. Consistent with this observation, the majority of luminal breast cancer cell lines are exquisitely sensitive to RSL3 with limited sensitivity to erastin. In RSL3-resistant, but not sensitive, luminal breast cancer cell lines, RSL3 induces HER2 pathway activation. Irreversible HER2 inhibitors including neratinib reversed RSL3 resistance in constitutively RSL3-resistant cell lines. Combination treatment with RSL3 and neratinib increases ferroptosis through mitochondrial iron-dependent reactive oxygen species production and lipid peroxidation. RSL3 also activated replication stress and concomitant S phase and G2/M blockade leading to sensitivity to targeting the DNA damage checkpoint. Together, our data support the exploration of RSL3 combined with irreversible HER2 inhibitors in clinical trials.© 2023. The Author(s).