Using Integrated Bioinformatics Analysis to Identify Saponin Formosanin C as a Ferroptosis Inducer in Colorectal Cancer with p53 and Oncogenic KRAS

Ferroptosis, a form of cell death, is characterized by lipid peroxidation and is dependent on iron and reactive oxygen species (ROS). Here, through bioinformatics analysis, formosanin C was predicted to be a ferroptosis inducer in colorectal cancer (CRC) by suppressing antioxidation capacity. Indeed, formosanin C induced iron accumulation, lipid ROS formation, and ferroptosis in CRC. We found that TP53 and KRAS were the second and third most frequently mutated genes in CRC and were associated with a poor prognosis. Analyses of differentially expressed genes indicated that fatty acid and labile iron levels tended to be higher in CRC than in normal tissues, suggesting the predisposition of CRC cells to ferroptosis. Transcriptomic analyses in CRC patients further identified that wild-type TP53 and mutant KRAS separately favored ferroptosis. Likewise, p53 knockdown rendered HCT 116 cells less sensitive to ferroptosis, and KRAS HT-29 cells were more sensitive to ferroptosis compared with their parental counterparts. Moreover, formosanin C synergistically enhanced chemosensitivity to cisplatin, and this process was mediated by lipid ROS. Overall, our novel gene-expression screening platform allows for the efficient identification of the biological function of novel phytochemicals, and the data suggest that formosanin C is an effective ferroptosis inducer in CRC cells with p53 or oncogenic KRAS.