Oridonin Alleviates Doxorubicin‐Induced Cardiotoxicity by Inhibiting p38 MAPK/MMP3 Signaling Pathway

ABSTRACT 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.