由于治疗选择有限，三阴性乳腺癌（TNBC）的预后较差。最近的研究表明，TNBC 高度依赖于线粒体氧化磷酸化。本研究的目的是探讨黄连碱（一种抑制线粒体电子传递链（ETC）复合物 I 的新型化合物）治疗 TNBC 的潜力。在本研究中，通过生物信息学分析了 TNBC 的线粒体代谢。进行体外和体内实验（小鼠）以评估黄连碱作为 ETC 复合物 I 靶向治疗剂的潜力，并研究黄连碱诱导的线粒体功能障碍的分子机制。在 TNBC 细胞和异种移植小鼠模型中评估黄连碱的治疗效果。我们证明线粒体 ETC I 是 TNBC 中这种代谢脆弱性的原因。此外，天然存在的化合物黄连碱对这种复合物 I 表现出特异性抑制活性。用黄连碱治疗可显着抑制线粒体功能，重新编程细胞代谢，诱导细胞凋亡并最终抑制 TNBC 细胞的增殖。此外，黄连碱给药诱导显着的生长抑制，这取决于异种移植小鼠模型中功能性复合物 I 的存在。总之，这些发现表明黄连碱作为有效的 ETC 复合物 I 抑制剂，针对 TNBC 的代谢脆弱性具有良好的潜力。© 2024 英国药理学会。

Triple-negative breast cancer (TNBC) has a poor prognosis due to limited therapeutic options. Recent studies have shown that TNBC is highly dependent on mitochondrial oxidative phosphorylation. The aim of this study was to investigate the potential of coptisine, a novel compound that inhibits the complex I of the mitochondrial electron transport chain (ETC), as a treatment for TNBC.In this study, mitochondrial metabolism in TNBC was analysed by bioinformatics. In vitro and in vivo experiments (in mice) were conducted to evaluate the potential of coptisine as an ETC complex I-targeting therapeutic agent and to investigate the molecular mechanisms underlying coptisine-induced mitochondrial dysfunction. The therapeutic effect of coptisine was assessed in TNBC cells and xenograft mouse model.We demonstrated that mitochondrial ETC I was responsible for this metabolic vulnerability in TNBC. Furthermore, a naturally occurring compound, coptisine, exhibited specific inhibitory activity against this complex I. Treatment with coptisine significantly inhibited mitochondrial functions, reprogrammed cellular metabolism, induced apoptosis and ultimately inhibited the proliferation of TNBC cells. Additionally, coptisine administration induced prominent growth inhibition that was dependent on the presence of a functional complex I in xenograft mouse models.Altogether, these findings suggest the promising potential of coptisine as a potent ETC complex I inhibitor to target the metabolic vulnerability of TNBC.© 2024 British Pharmacological Society.