Salviae Miltiorrhizae Radix et Rhizoma protects against doxorubicin-induced cardiotoxicity: A systematic review

Doxorubicin (DOX) is an effective first-line chemotherapeutic agent used to treat various kinds of cancers. The most serious side effect of DOX is its irreversible cardiotoxicity. Salviae Miltiorrhizae Radix et Rhizoma, which is the dry root of the natural plant Salvia miltiorrhiza and is named "Danshen" in Chinese, is a widely used Chinese Materia Medica for the treatment of cardiovascular and cerebrovascular disorders in traditional Chinese medicine. This study aims to review the potential protective effect of Danshen against DOX-induced cardiotoxicity (DIC). A comprehensive systematic search was performed in various electronic databases, including Web of Science, PubMed and Scopus up to July 2025 according to the PRISMA guideline. Two hundred and sixty studies were screened in accordance with a predefined set of inclusion and exclusion criteria. Thirty-five eligible articles were finally included in the current systematic review. All the characteristics and underlying mechanisms of Danshen protecting against DIC were summarized. Additionally, all the Danshen-related clinical trials evaluating their treatment effects for cardiovascular and cerebrovascular diseases were extracted and summarized from the registration databases of clinical trials. Danshen ameliorated DOX-caused pathological alterations of cardiac cells/tissue, decrease of surviving cardiomyocytes, body weight, heart weight and the ratio of heart to body weight, and increase of mortality. Eleven active ingredients and derivatives of Danshen including tanshinone IIA, sodium tanshinone IIA sulfonate, tanshinone I, salvianolic acid A, salvianolic acid B, salvianolic acid C, cryptotanshinone, ferulic acid, danshensu, dihydrotanshinone I and diethyl blechnic, were identified with potential protective effects against DIC in vitro and in vivo as well as the eight extracts and formulas of S. miltiorrhiza including salvianolic acids, S. miltiorrhiza aqueous extract, Compound DanShen Dripping Pill, Danhong injection, Qiliqiangxin, herbal formula B307, Qishen granule and Ershen Zhenwu Decoction. The underlying mechanisms were associated with the Danshen's multiple pharmacological activities, such as anti-apoptosis, anti-oxidative stress, anti-inflammation, anti-mitochondrial dysfunction, maintenance of intracellular Ca2+ homeostasis and regulating autophagy by targeting PI3K/Akt/JNK/GSK-3β/mPTP, MAPKs, Bax/Bcl-xL/Caspases, Keap1-Nrf2/NQO1/GPX4, SIRT3/Ac-SOD2, NF-κB, TGF-β/Smads, RhoA/ROCK, AMPK/PGC-1α/NRF-1/TFAM, miR-30a/Beclin1/LAMP1 signaling pathways. Moreover, Danshen-related clinical trials mainly focused on the treatment of cardiovascular and cerebrovascular diseases without clinical trials specifically for the evaluation of Danshen-related agents for the treatment of DIC. Danshen significantly alleviates DIC according to the previous experimental studies. But no previous study is implemented under cancer condition. A well-designed clinical study that targets certain cancer is an urgent requirement for the verification of Danshen's clinical efficacy in the future, in particular clarifying without affecting the anti-cancer efficacy of DOX.