SREBP2 confers ferroptosis resistance by targeting GPX4 in colorectal cancer

BACKGROUND: The upregulated expression of sterol regulatory element-binding protein 2 (SREBP2) has been observed in multiple types of malignant cancers. Ferroptosis is a form of cell death that is iron-dependent and driven by the accumulation of lipid peroxides. It has recently garnered considerable attention in Colorectal cancer (CRC) research. This study aims to investigate the role of SREBP2 in CRC ferroptosis resistance and the underlying molecular mechanisms. METHODS: SREBP2 expression was assessed in CRC. Functional assays were conducted in HT29 and RKO cells following SREBP2 knockdown or treatment with Betulin, the SREBP2 inhibitor. RNA-seq was used to screen the potential downstream targets of SREBP2. Mechanistically, ferroptosis-related markers and rescue assays revealed the relation between SREBP2 and CRC ferroptosis resistance mediated by GPX4 expression regulation. Furthermore, ChIP and luciferase assays were used to confirm the upstream that regulates SREBP2 expression. Finally, subcutaneous tumorigenesis model was employed to evaluate the therapeutic potential of targeting SREBP2 in CRC. RESULTS: The upregulated SREBP2 expression in CRC drives the proliferation, migration, and invasion of CRC cells. Mechanistically, SREBP2 directly increases GPX4 transcription, thereby reducing the sensitivity of CRC to ferroptosis and facilitating CRC progression. Additionally, β-catenin was identified as an upstream regulator of SREBP2. Inhibition of SREBP2 sensitizes CRC cells to ferroptosis and suppresses tumor growth. CONCLUSION: SREBP2 enhances ferroptosis resistance in CRC by upregulating GPX4, thereby contributing to tumor progression. Our findings highlight SREBP2 as a potential therapeutic target and provide a rationale for the development of SREBP2-targeted strategies in colorectal cancer.