ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2024; 20(7):2622-2639. doi:10.7150/ijbs.86479 This issue Cite
Research Paper
Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis
1. Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
2. Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150086, China.
3. Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.
4. Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China.
5. Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.
# Yilan Li, Jingru Yan and Heng Sun are contributed equally to this work.
Abstract
Sorafenib is a standard first-line drug for advanced hepatocellular carcinoma, but the serious cardiotoxic effects restrict its therapeutic applicability. Here, we show that iron-dependent ferroptosis plays a vital role in sorafenib-induced cardiotoxicity. Remarkably, our in vivo and in vitro experiments demonstrated that ferroptosis inhibitor application neutralized sorafenib-induced heart injury. By analyzing transcriptome profiles of adult human sorafenib-treated cardiomyocytes, we found that Krüppel-like transcription factor 11 (KLF11) expression significantly increased after sorafenib stimulation. Mechanistically, KLF11 promoted ferroptosis by suppressing transcription of ferroptosis suppressor protein 1 (FSP1), a seminal breakthrough due to its ferroptosis-repressing properties. Moreover, FSP1 knockdown showed equivalent results to glutathione peroxidase 4 (GPX4) knockdown, and FSP1 overexpression counteracted GPX4 inhibition-induced ferroptosis to a substantial extent. Cardiac-specific overexpression of FSP1 and silencing KLF11 by an adeno-associated virus serotype 9 markedly improved cardiac dysfunction in sorafenib-treated mice. In summary, FSP1-mediated ferroptosis is a crucial mechanism for sorafenib-provoked cardiotoxicity, and targeting ferroptosis may be a promising therapeutic strategy for alleviating sorafenib-induced cardiac damage.
Keywords: Sorafenib, Cardiotoxicity, Ferroptosis inhibitor, FSP1, GPX4, KLF11
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