Hou Xingyuan, Xie Suifen, Zhou Ni, Wei Shanshan, Yang Yuanying, Luo Ziheng, Liu Sa, Liu Jian, Xie Ning, Li Wenqun, Zhang Bikui
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Institute of Clinical Pharmacy, Central South University, Changsha, Hunan, China.
Chem Biol Drug Des. 2025 Mar;105(3):e70093. doi: 10.1111/cbdd.70093.
Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Oridonin (Ori), a bioactive component isolated from Isodon rubescens (Hemsl.) H. Hara, possesses potent anti-inflammatory and anticancer potentials. Therefore, our study aimed to evaluate the protective effects of Ori against DOX-induced cardiotoxicity. DIC models were established in vivo and in vitro. The action targets and pharmaceutical mechanism of Ori against DIC were comprehensively examined by network pharmacology, RNA-sequencing, and experimental validation. Ori relieved Dox-induced cell apoptosis in vitro and in vivo. A total of 7084 DEGs, 196 Ori, and 8172 DIC targets were screened by transcriptomics and network pharmacology, respectively. The three sets contained 11 intersection genes, including Ccl2, Myc, Mmp3, Egfr, p38 MAPK (MAPK14), Esr1, Tnf, Jun, Cdk1, Alb, and Ccnd1. The experimental results showed that Ori significantly decreased MMP-3 activity and the expression of p38 MAPK, thereby attenuating myocardial apoptosis and inflammatory infiltration. This study suggests that Ori is a potential therapeutic agent for DOX-induced cardiotoxicity that exerts its effects by inhibiting the p38 MAPK/MMP-3 signaling pathway.
尽管阿霉素（DOX）是一种治疗人类肿瘤的有效化疗药物，但严重的心脏毒性限制了其临床应用。冬凌草甲素（Ori）是从冬凌草中分离出的一种生物活性成分，具有强大的抗炎和抗癌潜力。因此，我们的研究旨在评估冬凌草甲素对阿霉素诱导的心脏毒性的保护作用。在体内和体外建立了阿霉素诱导的心脏毒性（DIC）模型。通过网络药理学、RNA测序和实验验证，全面研究了冬凌草甲素抗DIC的作用靶点和药理机制。冬凌草甲素在体内和体外均减轻了阿霉素诱导的细胞凋亡。通过转录组学和网络药理学分别筛选出7084个差异表达基因（DEGs）、196个冬凌草甲素作用靶点和8172个DIC靶点。这三组包含11个交集基因，包括Ccl2、Myc、Mmp3、Egfr、p38丝裂原活化蛋白激酶（MAPK14）、Esr1、Tnf、Jun、Cdk1、Alb和Ccnd1。实验结果表明，冬凌草甲素显著降低MMP-3活性和p38 MAPK表达，从而减轻心肌细胞凋亡和炎症浸润。本研究表明，冬凌草甲素是一种潜在的治疗阿霉素诱导心脏毒性的药物，其作用机制是通过抑制p38 MAPK/MMP-3信号通路实现的。
