Yang He, Wang Ling, Zhang Mengcheng, Wu Xingkang, Li Zhenyu, Ma Kaiqing
Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan, China.
Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, China.
Front Chem. 2024 Oct 3;12:1478674. doi: 10.3389/fchem.2024.1478674. eCollection 2024.
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.
酰基肉碱的积累是影响脂肪酸代谢的各种代谢紊乱的一个特征。尽管进行了广泛的研究，但尚未发现通过调节酰基肉碱代谢来诱导铁死亡的特定分子。在本研究中，基于对百部生物碱衍生物（SA-11）处理后的细胞代谢组学研究确定了酰基肉碱的积累，在我们之前的研究中已证明SA-11可诱导铁死亡。此外，证实肉碱棕榈酰转移酶-1（CPT-1）水平显著升高，而肉碱棕榈酰转移酶-2（CPT-2）水平无显著差异，这导致了酰基肉碱的积累。此外，添加外源性酰基肉碱显著增强了SA-11诱导铁死亡的能力，这可能是由于产生了额外的活性氧（ROS）。与对照组相比，在用SA-11处理的HCT-116细胞中观察到ROS水平升高，这一观察结果证实了这一假设。这些发现表明，靶向酰基肉碱代谢，特别是通过CPT-1，可能通过增强铁死亡诱导为癌症治疗提供一种新的治疗策略。
