Cardioprotective effect of Saussurea involucrata injection against Doxorubicin-induced cardiotoxicity by network pharmacology analysis and experimental verification

Abstract

Doxorubicin (Dox) is widely utilized in the clinical treatment of various cancers. Despite its efficacy, Dox induces numerous adverse effects in humans with significant cardiotoxicity, posing a major limitation to its use. Saussurea involucrata injection (SII), derived from Saussurea involucrata, exhibits notable anti-inflammatory and anti-oxidative stress properties. However, its potential protective effects against Dox-induced cardiotoxicity (DIC) remain unexplored. In this study, we investigate the ability of SII to mitigate DIC and elucidate the underlying mechanisms through experimental research and network pharmacology analysis. Results from both in vitro and in vivo experiments reveal that SII treatment significantly improves Dox-induced cardiac dysfunction, reducing pathological alterations and fibrosis in cardiomyocytes. Moreover, SII has cardioprotective effects by diminishing the inflammation, oxidative stress, and apoptosis triggered by Dox. Network pharmacological analysis further shows that SII downregulates P53 protein expression by activating the AKT/MDM2 signaling pathway, thus attenuating DIC. In conclusion, this study confirms that SII mitigates DIC through downregulation of the AKT/MDM2/P53 signaling pathway, suggesting a promising therapeutic strategy for alleviating DIC.

1. Introduction

Doxorubicin (Dox) is extensively employed as a chemotherapeutic agent to treat a range of malignancies [1], such as acute leukemia [2], non-Hodgkin's lymphoma [3], soft tissue sarcoma [4], and breast cancer [5]. Its clinical use has significantly increased cancer patient survival rates, establishing it as a cornerstone of cancer treatment. However, Dox induces various biochemical effects, especially cardiotoxicity, which can culminate in heart failure. Approximately 11% of patients experience Dox-induced cardiotoxicity (DIC) post-treatment, with the incidence being dose dependent: cumulative doses exceeding 400–700 mg/m2 in adults and 300 mg/m2 in children substantially increase the risk of heart failure. Chronic heart failure occurs in approximately 4% of patients receiving 500–550 mg/m2 cumulative doses, increasing to 18% at 600 mg/m2. This severe cardiotoxicity restricts its clinical application. Although the Food and Drug Administration of USA has approved the use of dexrazoxane (Dex) to mitigate DIC [6], its use is associated with complications, including exacerbated myelosuppression, a common adverse effect of chemotherapy [7]. Consequently, the medical community urgently seeks safe and effective therapies to reduce DIC.

Saussurea involucrata, a perennial herb from the Compositae family, is a rare and esteemed medicinal plant native to Xinjiang [8]. It thrives on the cliffs of the Tianshan Mountains at altitudes approximately 4000 m above sea level. For centuries, this herb has been a vital component of Chinese medicinal practices and, in the past fifty years, has gained broader application owing to its therapeutic properties, health benefits, and culinary uses [9]. According to the Pharmacopoeia of China, Saussurea involucrata injection (SII) is a sterile aqueous solution derived from the dried aerial parts of S. involucrata that has significant anti-inflammatory and anti-oxidative stress effects. For example, S. involucrata targets key proteins via MAPK- and NF-κB-related pathways to effectively inhibit inflammation and reduce bone destruction in the treatment of rheumatoid arthritis [10]. Moreover, SII modulates the Nrf2/HO-1/NLRP3 pathway to mitigate acute liver injury in mice [11]. Research has also highlighted the cardiovascular protective effects of S. involucrata.

The cardiotoxic mechanisms of Dox are complex and involve ROS production [12], inflammation promotion [13], apoptosis induction [14], mitochondrial impairment [15], endoplasmic reticulum stress, and autophagy pathway dysregulation [16]. Despite evidence that SII has anti-inflammatory, antioxidant, and cardioprotective properties, no studies have yet documented its potential to mitigate DIC. Therefore, this study aims to combine network pharmacology with in vivo and in vitro experiments to validate the efficacy of SII in alleviating DIC and elucidate the underlying mechanisms of its cardioprotective effects.