Chen Hsin-Chih, Chen Ching-Ying, Wang Pao-Yuan, Su Pin-Yu, Tsai Shu-Ping, Hsu Chi-Pei, Liu Hsiao-Sheng, Huang Chi-Ying F, Cheng Wen-Hsing, Lee Ming-Fen, Su Chun-Li
Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 10610, Taiwan.
Instrument Center, National Defense Medical University, Taipei 11490, Taiwan.
Antioxidants (Basel). 2025 Aug 21;14(8):1027. doi: 10.3390/antiox14081027.
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 and 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 and mutant 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.
铁死亡是一种细胞死亡形式，其特征在于脂质过氧化，并且依赖于铁和活性氧（ROS）。在这里，通过生物信息学分析，预测台湾杉素C通过抑制抗氧化能力成为结直肠癌（CRC）中的铁死亡诱导剂。事实上，台湾杉素C在CRC中诱导铁积累、脂质ROS形成和铁死亡。我们发现[基因名称1]和[基因名称2]是CRC中第二和第三最常发生突变的基因，并且与不良预后相关。差异表达基因分析表明，CRC中脂肪酸和不稳定铁水平往往高于正常组织，这表明CRC细胞易发生铁死亡。对CRC患者的转录组分析进一步确定，野生型[基因名称1]和突变型[基因名称2]分别有利于铁死亡。同样，p53基因敲低使HCT 116细胞对铁死亡的敏感性降低，而KRAS突变的HT-29细胞与其亲本细胞相比对铁死亡更敏感。此外，台湾杉素C协同增强对顺铂的化学敏感性，并且这个过程由脂质ROS介导。总体而言，我们新的基因表达筛选平台允许高效鉴定新型植物化学物质的生物学功能，并且数据表明台湾杉素C是具有p53或致癌性KRAS的CRC细胞中的有效铁死亡诱导剂。
