Chen Yi, Luo Wei, Wu Yanqing
Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang of Jiangxi, No. 1 Minde Road, Nanchang, Jiangxi 330006, China.
Department of Cardiology, The First People's Hospital of Nankang District, Ganzhou of Jiangxi, Xinkang East Avenue, Dongshan Street Office, Ganzhou, Jiangxi 341000, China.
Toxicol Appl Pharmacol. 2025 Feb;495:117179. doi: 10.1016/j.taap.2024.117179. Epub 2024 Dec 5.
Ferroptosis is a key process in doxorubicin (DOX)-induced cardiotoxicity and is a potentially important therapeutic target. Thymoquinone (TQ) is a monoterpenoid compound isolated from black cumin extract that exhibits antitumor effects and acts as a powerful mitochondrial-targeted antioxidant. In this study, we investigated the effect of TQ on DOX-induced cardiotoxicity and the potential underlying mechanisms.
Mice were randomly assigned to the control (CON) group, DOX (20 mg/kg) group, TQ10 (10 mg/kg/d) group, and TQ20 (20 mg/kg/d) group and intraperitoneally injected with DOX and different doses of TQ. The electrocardiogram, blood pressure, and cardiac ultrasound changes during the experiments showed that TQ exerted a protective effect against DOX-induced cardiotoxicity. The glutathione (GSH), malondialdehyde (MDA), and total antioxidant capacity (T-AOC) levels in the mouse heart tissue were significantly different from those in the CON group. Western blot analysis revealed that the expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in the DOX group was lower than that in the control group. TQ treatment decreased these changes, indicating that TQ alleviated DOX-induced cardiotoxicity and increased the antioxidant capacity of murine cardiomyocytes. The mechanism might involve activating the Nrf2/HO-1 signaling pathway and reducing iron-mediated death. Immunohistochemical staining revealed similar effects on the expression levels of NQO1, COX-2, and NOX4. Moreover, transmission electron microscopy indicated that TQ protected murine cardiomyocytes against DOX-induced mitochondrial damage.
The results of this study suggested that TQ can decrease oxidative stress levels and DOX-induced cardiotoxicity by activating the Nrf2/HO-1 signaling pathway to alleviate ferroptosis in murine cardiomyocytes.
铁死亡是阿霉素（DOX）诱导心脏毒性的关键过程，是一个潜在的重要治疗靶点。百里醌（TQ）是从黑种草提取物中分离出的一种单萜类化合物，具有抗肿瘤作用，是一种强大的线粒体靶向抗氧化剂。在本研究中，我们研究了TQ对DOX诱导的心脏毒性的影响及其潜在的作用机制。
将小鼠随机分为对照组（CON）、DOX（20mg/kg）组、TQ10（10mg/kg/d）组和TQ20（20mg/kg/d）组，腹腔注射DOX和不同剂量的TQ。实验期间的心电图、血压和心脏超声变化表明，TQ对DOX诱导的心脏毒性具有保护作用。小鼠心脏组织中的谷胱甘肽（GSH）、丙二醛（MDA）和总抗氧化能力（T-AOC）水平与CON组有显著差异。蛋白质免疫印迹分析显示，DOX组中核因子E2相关因子2（Nrf2）、血红素加氧酶-1（HO-1）、谷胱甘肽过氧化物酶4（GPX4）和铁蛋白重链1（FTH1）的表达低于对照组。TQ处理减轻了这些变化，表明TQ减轻了DOX诱导的心脏毒性，并提高了小鼠心肌细胞的抗氧化能力。其机制可能涉及激活Nrf2/HO-1信号通路并减少铁介导的死亡。免疫组织化学染色显示对NQO1、COX-2和NOX4的表达水平有类似影响。此外，透射电子显微镜表明，TQ保护小鼠心肌细胞免受DOX诱导的线粒体损伤。
本研究结果表明，TQ可通过激活Nrf2/HO-1信号通路降低氧化应激水平和DOX诱导的心脏毒性，从而减轻小鼠心肌细胞的铁死亡。
