需要有针对性的治疗策略来提高食管鳞状细胞癌(ESCC)患者的总体存活率和生活质量。核因子红细胞2相关因子2（NRF2）作为高可信度的癌症驱动基因，在癌症中控制抗氧化应答、代谢平衡和氧化还原稳态，被认为是癌症治疗的有效分子靶点。在这里，我们试图寻找一种新的NRF2抑制剂，并研究其在ESCC中的潜在分子机制。我们发现，上调的NRF2蛋白与患者预后呈负相关并促进ESCC中的肿瘤增殖。此外，已获FDA批准的药物Pizotifen Malate (PZM)结合到NRF2的Neh1结构域，并阻止NRF2蛋白结合到靶基因的ARE序列，抑制NRF2的转录活性。PZM处理通过下调GPX4、GCLC、ME1和G6PD的转录而诱导铁死亡，在ESCC PDX模型中抑制肿瘤发展。我们的研究表明，NRF2的过表达表明ESCC的预后不佳并促进肿瘤增殖。作为一种新型的NRF2抑制剂，PZM通过诱导铁死亡抑制肿瘤生长，并阐明了一种潜在的基于NRF2的ESCC治疗策略。 ©2023串联信号有限公司，独家授权施普林格自然出版集团有限公司。

Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.