Abstract
Doxorubicin (DOX) is a chemotherapeutic drug for a variety of malignancies, while its application is restricted by the cardiovascular toxic effects characterized by oxidative stress. Ferroptosis is a novel iron-dependent regulated cell death driven by lipid peroxidation. Our study aimed to investigate the role of Elabela (ELA) in DOX-induced oxidative stress and ferroptosis. In cultured rat aortic adventitial fibroblasts (AFs), stimulation with DOX dramatically induced cytotoxicity with reduced cell viability and migration ability, and enhanced lactate dehydrogenase (LDH) activity. Importantly, ELA and ferrostatin-1 (Fer-1) mitigated DOX-mediated augmentation of reactive oxygen species (ROS) in rat aortic AFs, accompanied by upregulated levels of Nrf2, SLC7A11, GPX4, and GSH. In addition, ELA reversed DOX-induced dysregulation of apoptosis- and inflammation-related factors including Bax, Bcl2, interleukin (IL)-1β, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Krüppel-like factor 15 (KLF15) by siRNA abolished ELA-mediated alleviation of ROS production and inflammatory responses. More importanly, KLF15 siRNA impeded the beneficial roles of ELA in DOX-pretreated rat aortic AFs by suppressing the Nrf2/SLC7A11/GPX4 signaling. In conclusion, ELA prevents DOX-triggered promotion of cytotoxicity, and exerts anti-oxidative and anti-ferroptotic effects in rat aortic AFs via activation of the KLF15/GPX4 signaling, indicating a promising therapeutic value of ELA in antagonizing DOX-mediated cardiovascular abnormality and disorders.
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Acknowledgements
This study was supported by the General Program and the National Major Research Plan Training Program of the National Natural Science Foundation of China (No. 92168117; 81770253; 91849111), Beijing Natural Science Foundation (7222068), Clinical Research Incubation Program of Beijing Chaoyang Hospital Affiliated to Capital Medical University (CYFH202209) and Reform and Development Program of Beijing Institute of Respiratory Medicine (ysrh2022002). We appreciate all graduate students and the doctors who participated in this study.
Funding
This study was supported by the General Program and the National Major Research Plan Training Program of the National Natural Science Foundation of China (No. 92168117; 81770253; 91849111), Beijing Natural Science Foundation (7222068), Clinical Research Incubation Program of Beijing Chaoyang Hospital Affiliated to Capital Medical University (CYFH202209) and Reform and Development Program of Beijing Institute of Respiratory Medicine (ysrh2022002).
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Mi-Wen Zhang and Jiu-Chang Zhong: writing—original draft, methodology, supervision, writing—review and editing, read and approved the final manuscript. Xue-Ting Li, Zhen-Zhou Zhang, and Ying Liu: collected and recorded the samples, methodology, read and approved the final manuscript. Jia-Wei Song and Xin-Ming Liu: collected and recorded the samples, read and approved the final manuscript. Yihang Chen, Ning Wang, and Ying Guo: formal analysis, read and approved the final manuscript. Li-Rong Liang and Jiu-Chang Zhong: Writing—review and editing, supervision, methodology, read and approved the final manuscript.
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Zhang, MW., Li, XT., Zhang, ZZ. et al. Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling. Cell Stress and Chaperones 28, 91–103 (2023). https://doi.org/10.1007/s12192-022-01317-6
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DOI: https://doi.org/10.1007/s12192-022-01317-6