铁死亡是一种由脂质过氧化引发的细胞死亡形式，已被证实为一种新的抗癌策略。癌细胞经常获得对铁死亡的抵抗能力，然而其潜在机制仍未被充分理解。为了解决这个问题，我们对来自数百个人类癌细胞系和原发组织样本的基因组和转录组数据进行了彻底的研究，特别关注了非小细胞肺癌（NSCLC）。观察发现，在NSCLC中，Kelch-like ECH-associated protein 1 (KEAP1)基因突变及其所导致的核因子红细胞2相关因子2 (NRF2, 也称为NFE2L2)激活与铁死亡抵抗强相关。此外，我们发现编码铁死亡抑制蛋白1 (FSP1)的AIFM2基因与铁死亡抵抗关联最显著，其次是多个NRF2靶基因。我们发现，仅抑制NRF2无法降低FSP1蛋白水平并促进铁死亡，而抑制FSP1有效地增加了KEAP1突变的NSCLC细胞对铁死亡的敏感性。此外，我们发现同时抑制FSP1和NRF2可以更强烈地诱导铁死亡。我们的研究结果表明，FSP1是铁死亡的关键抑制剂，其表达在一定程度上依赖NRF2，而同时靶向FSP1和NRF2可能是克服癌症对铁死亡的抵抗的有希望的策略。© 2023年。作者。

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming ferroptosis resistance in cancer.© 2023. The Author(s).