阿霉素（ADR）是临床应用广泛的有效的广谱抗肿瘤化学药物之一，可用于治疗成人和儿童的实体瘤和血液恶性肿瘤。然而，长期使用ADR会引起多种不良反应，包括时间和剂量依赖的心脏毒性，限制了其临床应用。此外，ADR诱导心脏毒性的机制仍不清楚。因此，我们使用斑马鱼作为动物模型，评估ADR毒性对胚胎心脏发育的影响，因为斑马鱼的胚胎心脏发育过程类似于人类的过程。斑马鱼胚胎暴露于1.25、2.5和5 mg/L的ADR会导致胚胎发育异常，出现心脏畸形、心包水肿、运动速度和活动减少以及静脉窦和动脉球之间距离（SV-BA）增加。ADR暴露导致前心肌中胚层形成期的心脏发育失调。我们还观察到心脏相关基因的不规则表达、凋亡基因表达的上调和氧化应激水平的剂量依赖性增加。此外，氧化应激诱导的凋亡对斑马鱼胚胎的心脏发育产生了有害影响，而天然色素虾青素（ATX）的治疗可以减轻这些心脏缺陷。ADR和Wnt途径相关基因具有很好的能量和空间匹配，ADR在斑马鱼中上调了Wnt信号通路。此外，IWR-1有效缓解了ADR引起的心脏缺陷。总之，我们证明了ADR对斑马鱼胚胎心脏发育的毒性作用可以为解释ADR诱导心脏毒性的发病机制提供理论依据，该作用通过上调氧化应激和Wnt信号通路发生，同时也为防治ADR诱导的心脏毒性提供了新思路。这些发现将有助于开发有效的治疗策略，以应对ADR诱导的心脏毒性，并拓展ADR在临床实践中的应用。 Copyright © 2023. Published by Elsevier Inc.

Adriamycin (ADR), one of the most effective broad-spectrum antitumor chemotherapeutic agents in clinical practice, is used to treat solid tumors as well as hematological malignancies in adults and children. However, long-term ADR use causes several adverse reactions, including time- and dose-dependent cardiotoxicity, which limit its clinical application. In addition, the mechanism by which ADR induces cardiotoxicity remains unclear. Therefore, we used zebrafish as animal models to evaluate ADR toxicity during embryonic heart development owing to the similarity of this process in zebrafish to that in humans. Exposure of zebrafish embryos to 1.25, 2.5, and 5 mg/L ADR induced abnormal embryonic development, with the occurrence of cardiac malformations, pericardial edema, decreased movement speed and activity, and increased distance between the venous sinus and the arterial bulb (SV-BA). ADR exposure induced dysregulated cardiogenesis during the precardiac mesoderm formation period. We also observed irregular expression of cardiac-related genes, an upregulation of apoptotic gene expression, and a dose-dependent increase in oxidative stress levels. Furthermore, oxidative stress-induced apoptosis exerted deleterious effects on cardiac development in zebrafish embryos, and treatment with astaxanthin (ATX) alleviated these heart defects. ADR- and Wnt pathway-related genes exhibited good energy and spatial matching, and ADR upregulated the Wnt signaling pathway in zebrafish. Moreover, IWR-1 effectively alleviated ADR-induced heart defects. In conclusion, we demonstrated that the toxic effects of ADR on cardiac development in zebrafish embryos could provide a theoretical basis for explaining the pathogenesis of ADR-induced cardiotoxicity, which occurs through the upregulation of oxidative stress and Wnt signaling pathway, as well as its prevention and treatment in humans. These findings will help develop effective treatment strategies to combat ADR-induced cardiotoxicity and broaden the application of ADR for clinical practice.Copyright © 2023. Published by Elsevier Inc.