Esophageal adenocarcinoma (EAC), the predominant type of esophageal cancer in the United States, develops through Barrett’s esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease, where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression to EAC. The NFE2-related factor 2 (NRF2) is the master cellular antioxidant regulator. We detected high NRF2 protein levels in the EAC cell lines and primary tissues. Knockdown of NRF2 significantly enhanced acidic bile salt-induced oxidative stress, DNA damage, and inhibited EAC cell growth. Brusatol, an NRF2 inhibitor, significantly inhibited NRF2 transcriptional activity and downregulated the NRF2 target genes. We discovered that in addition to inducing apoptosis, Brusatol alone or in combination with cisplatin (CDDP) induced significant lipid peroxidation and ferroptosis, as evidenced by reduced xCT and GPX4 expression, two known ferroptosis markers. The combination of Brusatol and CDDP significantly inhibited EAC tumor xenograft growth in vivo and confirmed the in vitro data showing ferroptosis as an important mechanism in the tumors treated with Brusatol or Brusatol and CDDP combination. Our data support the role of NRF2 in protecting against stress-induced apoptosis and ferroptosis in EACs. Targeting NRF2 in combination with platinum therapy can be an effective strategy for eliminating cancer cells in EAC.

中文翻译：

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靶向 NRF2 通过诱导铁死亡和细胞凋亡使食管腺癌细胞对顺铂敏感

食管腺癌 (EAC) 是美国食管癌的主要类型，通过巴雷特食管 (BE) - 不典型增生 - 癌级联发展。胃食管反流病（酸性胆汁盐反流入食管）是 BE 发生及其进展为 EAC 的主要危险因素。NFE2 相关因子 2 (NRF2) 是主要的细胞抗氧化调节剂。我们在 EAC 细胞系和原代组织中检测到高 NRF2 蛋白水平。NRF2 的敲低显着增强酸性胆汁盐诱导的氧化应激、DNA 损伤，并抑制 EAC 细胞生长。Brusatol 是一种 NRF2 抑制剂，可显着抑制 NRF2 转录活性并下调 NRF2 靶基因。我们发现，除了诱导细胞凋亡外，单独的 Brusatol 或与顺铂 (CDDP) 联合使用还可诱导显着的脂质过氧化和铁死亡，如 xCT 和 GPX4 表达（两种已知的铁死亡标记物）减少所证明的那样。Brusatol和CDDP的组合在体内显着抑制EAC肿瘤异种移植物生长，并证实了体外数据显示铁死亡是用Brusatol或Brusatol和CDDP组合治疗的肿瘤中的重要机制。我们的数据支持 NRF2 在防止 EAC 中应激诱导的细胞凋亡和铁死亡中的作用。靶向 NRF2 与铂类疗法相结合可能是消除 EAC 癌细胞的有效策略。