Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Research Center for Traceability and Standardization of TCMs, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, China.
Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
Int J Biol Sci. 2023 Jun 12;19(10):3077-3098. doi: 10.7150/ijbs.83392. eCollection 2023.
Looking for early diagnostic markers and therapeutic targets is the key to ensuring prompt treatment of myocardial ischemia (MI). Here, a novel biomarker xanthurenic acid (XA) was identified based on metabolomics and exhibited high sensitivity and specificity in the diagnosis of MI patients. Additionally, the elevation of XA was proved to induce myocardial injury by promoting myocardial apoptosis and ferroptosis. Combining metabolomics and transcriptional data further revealed that kynurenine 3-monooxygenase (KMO) profoundly increased in MI mice, and was closely associated with the elevation of XA. More importantly, pharmacological or heart-specific inhibition of KMO obviously suppressed the elevation of XA and profoundly ameliorated the OGD-induced cardiomyocytes injury and the ligation-induced MI injury. Mechanistically, KMO inhibition effectively restrained myocardial apoptosis and ferroptosis by modulating mitochondrial fission and fusion. In addition, virtual screening and experimental validation were adopted to identify ginsenoside Rb3 as a novel inhibitor of KMO and exhibited great cardioprotective effects by regulating mitochondrial dynamical balance. Taken together, targeting KMO may provide a new approach for the clinical treatment of MI through maintaining mitochondrial fusion and fission balance, and ginsenoside Rb3 showed great potential to be developed as a novel therapeutic drug targeting KMO.
寻找早期诊断标志物和治疗靶点是确保及时治疗心肌缺血（MI）的关键。在这里，基于代谢组学发现了一种新型生物标志物黄尿酸（XA），其在 MI 患者的诊断中具有高灵敏度和特异性。此外，研究证明 XA 的升高通过促进心肌细胞凋亡和铁死亡来诱导心肌损伤。代谢组学和转录组数据的结合进一步揭示，在 MI 小鼠中，犬尿氨酸 3-单加氧酶（KMO）显著增加，并且与 XA 的升高密切相关。更重要的是，通过抑制 KMO 的药理或心脏特异性抑制明显抑制了 XA 的升高，并显著改善了 OGD 诱导的心肌细胞损伤和结扎诱导的 MI 损伤。在机制上，KMO 抑制通过调节线粒体裂变和融合有效地抑制心肌细胞凋亡和铁死亡。此外，采用虚拟筛选和实验验证鉴定了人参皂苷 Rb3 作为 KMO 的新型抑制剂，通过调节线粒体动力学平衡显示出良好的心脏保护作用。总之，通过维持线粒体融合和裂变平衡，靶向 KMO 可能为 MI 的临床治疗提供新的方法，而人参皂苷 Rb3 作为一种新型靶向 KMO 的治疗药物具有很大的发展潜力。
