癌症干细胞（CSC）在癌症的发生和复发中发挥着重要作用。 CSC 中已记录了异常的铁和脂质代谢，这表明铁死亡（一种最近发现的以脂质过氧化为特征的受调节细胞死亡形式）可能对 CSC 产生重大影响。然而，铁死亡在胃癌干细胞（GCSC）中的确切作用仍不清楚。为了解决这一差距，我们使用癌症基因组图谱筛选了 GCSC 中与铁死亡相关的基因，并通过定量聚合酶链反应和蛋白质印迹证实了我们的发现。这些结果表明硬脂酰辅酶A去饱和酶（SCD1）是调节GCSCs铁死亡的关键角色。这项研究提供了证据，证明 SCD1 通过消除 P53 的转录抑制来正向调节角鲨烯环氧酶 (SQLE) 的转录。这种机制会增加胆固醇含量，而 SCD1 调节的胆固醇升高会通过 mTOR 信号通路抑制铁死亡。此外，我们的体内研究表明，SCD1 敲低或胆固醇摄入调节会影响 GCSC 的干性及其对铁死亡诱导剂的敏感性。因此，靶向 SCD1/角鲨烯环氧酶/胆固醇信号轴与铁死亡诱导剂相结合可能代表一种基于 GCSC 的有前景的胃癌治疗方法。版权所有 © 2024。由 Elsevier B.V 出版。

Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.Copyright © 2024. Published by Elsevier B.V.