Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway

Hang Chen; Ji Zhu; Yifei Le; Jieli Pan; Ying Liu; Zhijun Liu; Cui Wang; Xiaobing Dou; Dezhao Lu

doi:10.1016/j.phymed.2022.153964

Salidroside inhibits doxorubicin-induced cardiomyopathy by modulating a ferroptosis-dependent pathway

Phytomedicine. 2022 May:99:153964. doi: 10.1016/j.phymed.2022.153964. Epub 2022 Jan 29.

Authors

Hang Chen¹, Ji Zhu², Yifei Le¹, Jieli Pan³, Ying Liu¹, Zhijun Liu¹, Cui Wang¹, Xiaobing Dou¹, Dezhao Lu⁴

Affiliations

¹ School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
² The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhongshan Hospital of Zhejiang Province), Hangzhou 330106, China.
³ Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
⁴ School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: ludezhao@126.com.

PMID: 35180677
DOI: 10.1016/j.phymed.2022.153964

Abstract

Background: Doxorubicin-induced cardiotoxicity (DIC) limits the clinical application of the drug in treatment of cancers and imposes a severe health burden on the patients. Therefore, there is an urgent need to develop alternative therapeutic strategies or drugs to minimize DIC. Salidroside is a phenylpropanoid glycoside extracted from Rhodiola rosea with multiple biological effects such as anti-inflammation and antioxidant properties. However, its mechanism of action in DIC is still poorly understood.

Purpose: The present study was aimed to investigate the role of salidroside in DIC and associated mechanism of action for the described effects.

Methods: Cardiac dysfunction was induced through treatment of mice with doxorubicin in vivo and in vitro. The mechanism of action of salidroside was investigated using western blot assay, qPCR, immunofluorescence, histochemistry, echocardiography, and high-content imaging system.

Results: Results of the current study found that treatment of mice with salidroside significantly improved doxorubicin-induced cardiac dysfunction, ferroptosis-like cell damage, and fibrosis in vivo. Further, it was noted that salidroside inhibited ferroptosis in vivo and in vitro by limiting iron accumulation, restoring GPX4-dependent antioxidant capacity, and preventing lipid peroxidation at the cellular or mitochondrial levels. Mechanistically, salidroside inhibited DOX-induced mitochondrial ROS, Fe²⁺, and lipid peroxidation as well as restored mitochondrial membrane potential by promoting mitochondrial biogenesis, improving mitochondrial iron-sulfur clusters, and restoring mitochondrial OXPHOS complexes, thereby improving mitochondrial function. In addition, AMPK is a key protein that coordinates mitochondria, metabolism, and ferroptosis. Therefore, it was found that compound C (CC), an AMPK inhibitor, disrupted the regulation of cellular lipid metabolism and mitochondrial function of salidroside as well as led to failure of the protective effect of salidroside against ferroptotic cell death.

Conclusions: The present study evidently demonstrated the cardioprotective effects of salidroside against doxorubicin-induced cardiomyopathy. Further, salidroside markedly down-regulated ferroptotic cell death by activating AMPK-dependent signaling pathways including regulating abnormal fatty acid metabolism and maintaining mitochondrial function. Therefore, salidroside is can be exploited to develop a novel medication for clinical DIC and salidroside may represent a novel treatment that improves recovery from DIC by targeting ferroptosis.

Keywords: AMPK signaling pathway; Cardiomyocytes; Doxorubicin-induced cardiomyopathy; Ferroptosis, Salidroside; Mitochondria.