Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.

中文翻译：

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BRCA1 介导的铁死亡的双重调节暴露了 BRCA1 缺陷癌症中 GPX4 和 PARP 共抑制的脆弱性

对聚 (ADP-核糖) 聚合酶抑制剂 (PARPi) 的耐药性限制了 PARP 抑制在治疗乳腺癌易感基因 1 (BRCA1) 缺陷型癌症中的治疗效果。在这里，我们揭示了 BRCA1 在调节铁死亡中具有双重作用。 BRCA1 促进电压依赖性阴离子通道 3 (VDAC3) 和谷胱甘肽过氧化物酶 4 (GPX4) 的转录；因此，BRCA1 缺陷会促进细胞对erastin诱导的铁死亡的抵抗，但会使癌细胞对GPX4抑制剂（GPX4i）诱导的铁死亡敏感。此外，在 PARPi 和 GPX4i 共同治疗后，核受体共激活剂 4 (NCOA4) 介导的铁蛋白自噬和 GPX4 诱导缺陷会在 BRCA1 缺陷癌细胞中引发强效铁死亡。最后，我们发现源自具有 PARPi 耐药性的 BRCA1 突变乳腺癌患者的异种移植肿瘤表现出 GPX4 表达降低以及对 PARP 和 GPX4 共抑制的高敏感性。我们的结果表明，BRCA1 缺陷会导致对 PARP 和 GPX4 共同抑制的铁死亡脆弱性，并为克服 BRCA1 缺陷癌症中的 PARPi 耐药性的治疗策略提供了信息。