Ferroptosis inhibitor alleviates sorafenib-induced cardiotoxicity by attenuating KLF11-mediated FSP1-dependent ferroptosis

• Published in: International journal of biological sciences Vol. 20; no. 7; pp. 2622 - 2639
• Main Authors: Li, Yilan, Yan, Jingru, Sun, Heng, Liang, Yating, Zhao, Qianqian, Yu, Shan, Zhang, Yao
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2024
• Subjects: Animals; Cardiotoxicity - etiology; Cardiotoxicity - metabolism; Ferroptosis - drug effects; Humans; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Research Paper; S100 Calcium-Binding Protein A4 - genetics; S100 Calcium-Binding Protein A4 - metabolism; Sorafenib - adverse effects; KLF11; Cardiotoxicity; GPX4; Sorafenib; FSP1; Ferroptosis inhibitor
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.86479

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 and 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.