Original ArticleSaikosaponin D Alleviates DOX-induced Cardiac Injury In Vivo and In VitroZhang, Yan-Jing MD*; Wu, Si-Si PhD*; Chen, Xue-Mei MD*; Pi, Jin-Kui MD*; Cheng, Yu-Fei MD*; Zhang, Yi BS*; Wang, Xiao-Jiao MD*; Luo, Dan MD*; Zhou, Jin-Han MD*; Xu, Jia-Yi MD*; Li, Xue MD†; Wu, Zhuang MD†; Jiang, Wei PhD†; Wang, Xiao-Xiao PhD‡ Author Information *Core Facilities, West China Hospital, Sichuan University, Chengdu, People's Republic of China; †Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China; and ‡Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, People's Republic of China. Correspondence: Xiao-Xiao Wang, PhD, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, People's Republic of China (e-mail: [email protected]). Supported by Chongqing Research Institute Performance Incentive Guidance Special Project (cstc2019jxjl130018), the National Natural Science Foundation of China (81700229), and Scientific research topic of Sichuan Provincial Health and Health Commission (20ZD004). The construction project of the key specialty of Chongqing clinical pharmacy. The authors report no conflicts of interest. Y. -J. Zhang and S.-S. Wu contributed equally to this work. Journal of Cardiovascular Pharmacology: April 2022 - Volume 79 - Issue 4 - p 558-567 doi: 10.1097/FJC.0000000000001206 Buy Metrics Abstract As a highly efficient anticancer agent, doxorubicin (DOX) is used for treatment of various cancers, but DOX-induced oxidative damages contribute to a degenerative irreversible cardiac toxicity. Saikosaponin D (SSD), which is a triterpenoid saponin with many biological activities including anti-inflammatory effects and antioxidant properties, provides protection against pathologic cardiac remodeling and fibrosis. In the present study, we investigated the work of SSD for DOX-induced cardiotoxicity and the involved mechanisms. We observed that DOX injection induced cardiac injury and malfunction and decreased survival rate. Besides, DOX treatment increased lactate dehydrogenase leakage, cardiomyocyte apoptosis, and myocardium fibrosis and decreased the size of cardiomyocytes. Meanwhile, all the effects were notably attenuated by SSD treatment. In vitro, we found that 1 μM SSD could enhance the proliferation of H9c2 cells and inhibit DOX-induced apoptosis. It was found that the levels of malondialdehyde (MDA) and reactive oxygen species were significantly reduced by improving the activities of the endogenous antioxidative enzymes including catalase and glutathione peroxidase. Furthermore, SSD treatment could downregulate the DOX-induced p38 phosphorylation. Our results suggested that SSD efficiently protected the cardiomyocytes from DOX-induced cardiotoxicity by inhibiting the excessive oxidative stress via p38-MAPK (mitogen-activated protein kinase, MAPK) signaling pathway. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.