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.

铁死亡是一种由脂质过氧化诱导的细胞死亡，已成为一种新型的抗癌策略。癌细胞经常获得对铁死亡的抵抗力。然而，人们对潜在机制知之甚少。为了解决这个问题，我们对来自数百个人类癌细胞系和原代组织样本的基因组和转录组数据进行了彻底的研究，特别关注非小细胞肺癌（NSCLC）。据观察，Kelch 样 ECH 相关蛋白 1 ( KEAP1 ) 的突变和随后的核因子红细胞 2 相关因子 2 (NRF2，也称为 NFE2L2) 激活与 NSCLC 中的铁死亡抵抗密切相关。此外，编码铁死亡抑制蛋白 1 (FSP1) 的AIFM2基因被确定为与铁死亡抗性最显着相关的基因，其次是多个 NRF2 靶标。我们发现单独抑制 NRF2 不足以降低 FSP1 蛋白水平并促进铁死亡，而 FSP1 抑制有效地使KEAP1突变 NSCLC 细胞对铁死亡敏感。此外，我们发现 FSP1 和 NRF2 的联合抑制会更强烈地诱导铁死亡。我们的研究结果表明，FSP1 是铁死亡的重要抑制因子，其表达部分依赖于 NRF2，并且协同靶向 FSP1 和 NRF2 可能是克服癌症中铁死亡抵抗的有前途的策略。