Abstract：
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.
摘要：
癌症干细胞（CSC）在癌症发作和复发中起重要作用。反常的铁和脂质代谢已被证明在CSC，表明铁性凋亡，最近发现的一种以脂质过氧化为特征的调节细胞死亡形式，可能对CSC产生重大影响。然而,铁凋亡在胃癌干细胞(GCSCs)中的确切作用尚不清楚.为了解决这个差距，我们使用癌症基因组图谱筛选了GCSCs中的铁凋亡相关基因,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GCSC中铁凋亡调节的关键参与者。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。该机制增加胆固醇含量,并且由SCD1调节的升高的胆固醇通过mTOR信号通路抑制铁凋亡。此外，我们的体内研究表明,SCD1敲除或胆固醇摄入的调节会影响GCSCs的干性及其对铁凋亡诱导物的敏感性.因此，靶向SCD1/角鲨烯环氧酶/胆固醇信号轴与铁凋亡诱导物联合可能代表基于GCSC治疗胃癌的有希望的治疗方法.
