治疗抵抗和转移是癌症中最致命的步骤，通常是由上皮间质转化 (EMT) 程序的（部分）激活引发的。间充质表型易发生铁死亡，这是一种由铁和氧自由基介导的含有多不饱和脂肪酸的磷脂过氧化作用所产生的细胞死亡途径。我们在这里表明，各种形式的 EMT 激活，包括 TGFβ 刺激和获得性治疗抵抗，会增加癌细胞铁死亡的易感性，这取决于 EMT 转录因子 Zeb1。我们证明，Zeb1 通过调节潜在关键酶硬脂酰辅酶 A 去饱和酶 1 (SCD)、脂肪酸合酶 (FASN) 的差异表达，增加了含有促铁死亡多不饱和脂肪酸的磷脂与细胞保护性单不饱和脂肪酸的比例。 、脂肪酸去饱和酶 2 (FADS2)、极长链脂肪酸延伸酶 5 (ELOVL5) 和长链酰基辅酶 A 合成酶 4 (ACSL4)。对选定的脂肪生成酶（SCD 和 FADS2）进行药理学抑制，可以优先在高 Zeb1 表达的癌细胞中操纵铁死亡敏感性。我们的数据具有潜在的转化相关性，并建议结合使用铁死亡激活剂和 SCD 抑制剂来治疗表达高 Zeb1 的侵袭性癌症。© 2024。作者。

Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1.© 2024. The Author(s).