SCD1 promotes the stemness of gastric cancer stem cells by inhibiting ferroptosis through the SQLE/cholesterol/mTOR signalling pathway

• Published in: International journal of biological macromolecules 2024-08, Vol.275 (Pt 2), p.133698, Article 133698
• Main Authors: Mao, Xinyuan, Wang, Lingzhi, Chen, Zhian, Huang, Huilin, Chen, Jialin, Su, Jin, Li, Zhenhao, Shen, Guodong, Ren, Yingxin, Li, Zhenyuan, Wang, Weisheng, Ou, Jinzhou, Guo, Weihong, Hu, Yanfeng
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cholesterol - metabolism; Cholesterol biosynthesis; Ferroptosis; Ferroptosis - genetics; Gastric cancer; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; SCD1; Signal Transduction; Squalene Monooxygenase - genetics; Squalene Monooxygenase - metabolism; Stearoyl-CoA Desaturase - genetics; Stearoyl-CoA Desaturase - metabolism; Stemness; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.133698

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. •SCD1 can play a role in the regulation of ferroptosis by regulating cholesterol metabolism.•Gastric cancer stem cells exhibit aberrant cholesterol metabolism.•The elevated cholesterol levels induced by SCD1 facilitate the resistance of gastric cancer stem cells against ferroptosis via the mTOR signaling pathway.