Doxorubicin（DOX）是一种有效的抗肿瘤药物，但其心毒性严重限制了其临床应用。有趣的是，有一个假设表明DOX诱导的心毒性与线粒体疾病和氧化应激之间存在关联。线粒体酸5（MA5）通过促进线粒体ATP合成和减少活性氧积累，显示出缓解线粒体功能障碍的潜力，但其在改善DOX诱导的心毒性方面的潜力尚不明确。本研究采用网络药理学方法、分子对接技术和分子动力学模拟（MDS）揭示了MA5在治疗DOX诱导的心毒性中的特定药物靶标和药理机制。为了进行实验验证，心肌细胞（H9c2）和小鼠在DOX存在或不存在的情况下接受MA5暴露。我们的研究涉及了超声心动图参数、心肌酶、炎症因子、线粒体功能、心肌结构和心肌细胞凋亡的评估。在网络药理学中鉴定的100个核心靶标中，MA5通过与癌症、前列腺癌、脂质和动脉粥样硬化相关的途径，在治疗DOX诱导的心毒性方面表现出药理活性。分子对接分析确认了MA5与TNF-α、白细胞介素-6（IL-6）和半胱天冬酶-3的良好对接性。此外，MA5对TNF-α的亲和力高于IL-6和半胱天冬酶-3。进一步的MDS揭示了MA5与TNF-α之间的结合稳定性。DOX受挑战的小鼠显示异常的心肌酶谱、破坏性收缩功能和舒张功能，以及升高的炎症和心肌细胞凋亡，MA5的给予可以减轻这些异常。同样，DOX暴露的H9c2细胞显示出细胞内ROS产生增加和线粒体功能受损，MA5的治疗可以缓解这些症状。我们的研究结果表明，MA5通过TNF-α介导的炎症和凋亡调控减轻DOX诱导的心脏异常。这些结果为管理DOX诱导的心脏并发症提供了潜在的治疗策略，从而提高了癌症治疗的安全性和有效性。版权所有©2023 Elsevier B.V.保留所有权利。

Doxorubicin (DOX) is an effective anti-tumor drug, but the cardiotoxicity severely limits its clinical use. Interestingly, a hypothesis has emerged suggesting an association between DOX-induced cardiotoxicity and mitochondrial disorders and oxidative stress. The mitochonic acid 5 (MA5) shows promise in alleviating mitochondrial dysfunction by promoting mitochondrial ATP synthesis and reducing reactive oxygen species (ROS) accumulation, though its potential in ameliorating DOX-induced cardiotoxicity remains elusive.Network pharmacology approach, molecular docking techniques, and molecular dynamics simulation (MDS) were used to reveal the specific drug targets and pharmaceutical mechanisms involved in the treatment of DOX-induced cardiotoxicity using MA5. For experimental verification, cardiomyocytes (H9c2) and mice were exposed to DOX in the presence or absence of MA5. Our investigation involved the assessment of echocardiographic parameters, cardiac enzymes, inflammatory factors, mitochondrial function, myocardial structure, and cardiomyocyte pyroptosis.Among the 100 core targets identified in network pharmacology, MA5 was pharmacologically active against DOX-induced cardiotoxicity via pathways implicated in cancer, prostate cancer, lipids and atherosclerosis. Molecular docking analysis confirmed that MA5 docked well with TNF-α, interleukin-6 (IL-6), and caspase-3. Furthermore, MA5 exhibited a stronger affinity toward TNF-α than IL-6 and caspase-3. Subsequent MDS revealed the stability of binding between MA5 and TNF-α. The DOX-challenged mice also displayed abnormal myocardial enzymogram, disrupted systolic and diastolic function, and elevated inflammation and cardiomyocyte pyroptosis, which could be mitigated by the administration of MA5. Similarly, H9c2 cells exposed to DOX showed increased intracellular ROS production and impaired mitochondrial function, which were relieved by MA5 treatment.Our findings suggest that MA5 attenuates DOX-induced cardiac anomalies through the TNF-α-mediated regulation of inflammation and pyroptosis. These insights offer a potential therapeutic strategy for managing DOX-induced cardiac complications, thereby improving the safety and efficacy of cancer treatments.Copyright © 2023 Elsevier B.V. All rights reserved.