花蟾素胶囊（HCSc）是一种简单的肠溶胶囊，由传统药材蟾蜍皮精制而成。临床多年来用于治疗多种恶性肿瘤，疗效显着。目前，HCSc的多种主要成分已被报道具有心脏毒性，但其心脏毒性的具体机制仍不清楚。本研究的目的是阐明HCSc在临床应用中的不良反应，明确HCSc的主要毒性成分。 HCSc及其引起心脏毒性的机制。利用UPLC-Q-Exactive Orbitrap MS和网络毒理学来识别和预测潜在的毒性成分、相关信号通路。然后，我们通过急性和亚急性毒性实验揭示了HCSc引起的明显心脏毒性现象。最后，我们结合转录组学和代谢组学阐明了其潜在的作用机制，并通过分子对接、RT-qPCR和Western blot验证了推测的机制。我们发现8种蟾蜍二烯内酯成分可能是引起HCSc心脏毒性的主要毒性成分。通过毒性实验，我们发现高剂量HCSc可使多种血常规指标、五种心肌酶、心力衰竭指标（BNP）、肌钙蛋白（cTnI和cTnT）、心率和心脏组织损伤程度升高。另外，通过分子对接，发现8种主要毒性成分与cAMP、AMPK、IL1β、mTOR都可以很好的结合，尤其是cAMP。同时，RT-qPCR和Western blot结果表明，HCSc可以通过调节多种心脏相关差异基因、激活cAMP信号通路来诱导心脏毒性。本研究利用网络毒理学、转录组学和代谢组学来阐明HCSc的复杂机制。高剂量 HCSc 引起的心脏毒性。还利用动物实验、分子对接、Western blot和RT-qPCR实验来验证上述机制。这些发现将为进一步的机理研究提供信息，并为其安全临床应用提供理论支持。版权所有 © 2024。由 Elsevier B.V. 出版。

Huachansu Capsule (HCSc) is a simple enteric-coated capsule refined from the skin of the dried toad, a traditional medicinal herb. It has been used clinically for many years to treat a variety of malignant tumors with remarkable efficacy. To date, a number of main components of HCSc have been reported to be cardiotoxic, but the specific mechanism of cardiotoxicity is still unknown.The aim of this study is to elucidate the adverse effects of HCSc in clinical application, clarify the main toxic components of HCSc and the mechanism of cardiotoxicity caused by HCSc.UPLC-Q-Exactive Orbitrap MS and network toxicology were used to identify and predict the potential toxic components, related signaling pathways. Then, we used acute and subacute toxicity experiments to reveal the apparent phenomenon of HCSc-induced cardiotoxicity. Finally, we combined transcriptomics and metabolomics to elucidate the potential mechanism of action, and verified the putative mechanism by molecular docking, RT-qPCR, and Western blot.We found 8 toad bufadienolides components may be induced cardiac toxicity HCSc main toxic components. Through toxicity experiments, we found that high dose of HCSc could increase a variety of blood routine indexes, five cardiac enzymes, heart failure indexes (BNP), troponin (cTnI and cTnT), heart rate and the degree of heart tissue damage. In addition, by molecular docking, found that 8 kinds of main toxic components and cAMP, AMPK, IL1β, mTOR all can be a very good combination, especially in the cAMP. Meanwhile, RT-qPCR and Western blot results showed that HCSc could induce cardiotoxicity by regulating a variety of heart-related differential genes and activating the cAMP signaling pathway.In this study, network toxicology, transcriptomics and metabolomics were used to elucidate the complex mechanism of high-dose HCSc-induced cardiotoxicity. Animal experiments, molecular docking, Western blot and RT-qPCR experiments were also used to verify the above mechanism. These findings will inform further mechanistic studies and provide theoretical support for its safe clinical application.Copyright © 2024. Published by Elsevier B.V.