德国埃尔兰根-纽伦堡弗里德里希-亚历山大大学Thomas Brabletz和奥地利因斯布鲁克大学Andreas Koeberle共同合作，近期取得重要工作进展。他们研究提出，Zeb1通过调节脂肪生成酶表达和磷脂组成介导癌症细胞EMT相关的铁死亡敏感性。相关研究成果2024年7月15日在线发表于《自然—细胞生物学》杂志上。

据介绍，治疗耐药性和转移是癌症最致命的步骤，通常由上皮-间质转化（EMT）程序的（部分）激活触发。间充质表型易导致铁死亡，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引起的细胞死亡途径。

研究人员发现，各种形式的EMT激活，包括TGFβ刺激和获得性治疗耐药性，增加了癌症细胞对铁死亡的易感性，这取决于EMT转录因子Zeb1。研究表明，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）、脂肪酸酯去饱和酶2（FADS2）、超长链脂肪酸延长5（ELOVL5）和长链酰基辅酶A合成酶4（ACSL4）的差异表达，增加了含有亲铁性多不饱和脂肪酸的磷脂比含有细胞保护性单不饱和脂肪酸的磷脂比例。对所选脂肪生成酶（SCD和FADS2）的药理学抑制允许优先在高表达Zeb1的癌症细胞中操纵铁死亡敏感性。

总之，这一研究数据具有潜在的翻译相关性，表明铁死亡激活剂和SCD抑制剂的组合可用于治疗表达高Zeb1的侵袭性癌症。

附：英文原文

Title: Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition

Author: Schwab, Annemarie, Rao, Zhigang, Zhang, Jie, Gollowitzer, Andr, Siebenks, Katharina, Bindel, Nino, DAvanzo, Elisabetta, van Roey, Ruthger, Hajjaj, Yussuf, zel, Ece, Armstark, Isabell, Bereuter, Leonhard, Su, Fengting, Grander, Julia, Bonyadi Rad, Ehsan, Groenewoud, Arwin, Engel, Felix B., Bell, George W., Henry, Whitney S., Angeli, Jos Pedro Friedmann, Stemmler, Marc P., Brabletz, Simone, Koeberle, Andreas, Brabletz, Thomas

Issue&Volume: 2024-07-15

Abstract: 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.

DOI: 10.1038/s41556-024-01464-1

Source: https://www.nature.com/articles/s41556-024-01464-1