Table1_Stemona alkaloid derivative induce ferroptosis of colorectal cancer cell by mediating carnitine palmitoyltransferase 1.XLSX

Accumulation of acylcarnitines is a characteristic feature of various metabolic disorders affecting fatty acid metabolism. Despite extensive research, no specific molecules have been identified to induce ferroptosis through the regulation of acylcarnitine metabolism. In this study, acylcarnitine accumulation was identified based on cell metabolomics study after the treatment with Stemona alkaloid derivative (SA-11), which was proved to induce ferroptosis in our previous research. Furthermore, the CPT-1 level was proved to significantly increase, while the CPT-2 level indicated no significant difference, which resulted in the accumulation of acylcarnitine. Besides, the ferroptosis-inducing ability of SA-11 was significantly enhanced by the addition of exogenous acylcarnitine, presumably due to the production of additional ROS. This hypothesis was corroborated by the observation of increased ROS levels in HCT-116 cells treated with SA-11 compared to the control group. These findings suggest that targeting acylcarnitine metabolism, particularly through CPT-1, may offer a novel therapeutic strategy for cancer treatment by enhancing ferroptosis induction.

酰基肉碱（acylcarnitines）的蓄积是多种影响脂肪酸代谢的代谢紊乱的典型特征。尽管已有大量研究，但尚未发现可通过调控酰基肉碱代谢诱导铁死亡（ferroptosis）的特异性分子。本研究通过对经百部生物碱衍生物（Stemona alkaloid derivative, SA-11）处理的细胞开展代谢组学分析，鉴定出了酰基肉碱蓄积现象——此前本团队的研究已证实SA-11可诱导铁死亡。进一步研究发现，肉碱棕榈酰转移酶1（CPT-1）的表达水平显著升高，而肉碱棕榈酰转移酶2（CPT-2）的表达水平则无显著变化，这一差异最终导致了酰基肉碱的蓄积。此外，外源性添加酰基肉碱可显著增强SA-11的铁死亡诱导能力，推测这一现象与活性氧（reactive oxygen species, ROS）生成增多有关。对经SA-11处理的HCT-116细胞的观测结果证实了这一假说：其ROS水平较对照组显著升高。上述研究结果表明，靶向调控酰基肉碱代谢（尤其是通过调控CPT-1），有望通过增强铁死亡诱导效应，为癌症治疗提供全新的治疗策略。