Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity

Lexin Shu; Yuming Wang; Wei Huang; Simiao Fan; Junhua Pan; Qingbo Lv; Lin Wang; Yujing Wang; Jinpeng Xu; Haifeng Yan; Yuchao Bai; Yi Wang; Yubo Li

doi:10.1021/acsomega.3c01441

Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Tongmai Yangxin Pills in Ameliorating Doxorubicin-Induced Cardiotoxicity

ACS Omega. 2023 May 8;8(20):18128-18139. doi: 10.1021/acsomega.3c01441. eCollection 2023 May 23.

Authors

Lexin Shu¹, Yuming Wang¹, Wei Huang¹, Simiao Fan¹, Junhua Pan², Qingbo Lv³, Lin Wang⁴, Yujing Wang⁴, Jinpeng Xu⁵, Haifeng Yan³, Yuchao Bai¹, Yi Wang³, Yubo Li¹

Affiliations

¹ School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
² Hainan Province Key Laboratory for Drug Preclinical Study of Pharmacology and Toxicology Research, Hainan Medical University, Haikou 571199, China.
³ Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
⁴ Tianjin Zhongxin Pharmaceutical Group Co., Ltd., Le Ren Tang Pharmaceutical Factory, Tianjin 301617, China.
⁵ Tianjin Zhongxin Pharmaceutical Group Co., Ltd., Tianjin 301617, China.

Abstract

Doxorubicin (DOX) is a broad-spectrum chemotherapeutic drug used in clinical treatment of malignant tumors. It has a high anticancer activity but also high cardiotoxicity. The aim of this study was to explore the mechanism of Tongmai Yangxin pills (TMYXPs) in ameliorating DOX-induced cardiotoxicity through integrated metabolomics and network pharmacology. In this study, first, an ultrahigh-performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry (UPLC-Q-TOF/MS) metabonomics strategy was established to obtain metabolite information and potential biomarkers were determined after data processing. Second, network pharmacological analysis was used to evaluate the active components, drug-disease targets, and key pathways of TMYXPs to alleviate DOX-induced cardiotoxicity. Targets from the network pharmacology analysis and metabolites from plasma metabolomics were jointly analyzed to select crucial metabolic pathways. Finally, the related proteins were verified by integrating the above results and the possible mechanism of TMYXPs to alleviate DOX-induced cardiotoxicity was studied. After metabolomics data processing, 17 different metabolites were screened, and it was found that TMYXPs played a role in myocardial protection mainly by affecting the tricarboxylic acid (TCA) cycle of myocardial cells. A total of 71 targets and 20 related pathways were screened out with network pharmacological analysis. Based on the combined analysis of 71 targets and different metabolites, TMYXPs probably played a role in myocardial protection through regulating upstream proteins of the insulin signaling pathway, MAPK signaling pathway, and p53 signaling pathway, as well as the regulation of metabolites related to energy metabolism. They then further affected the downstream Bax/Bcl-2-Cyt c-caspase-9 axis, inhibiting the myocardial cell apoptosis signaling pathway. The results of this study may contribute to the clinical application of TMYXPs in DOX-induced cardiotoxicity.