Liu 2023 Pharmacol Res

Liu S, Yue S, Guo Y, Han JY, Wang H (2023) Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes. https://doi.org/10.1016/j.phrs.2023.107017

» Pharmacol Res [Epub ahead of print]. PMID: 38006979 Open Access

Liu Songming, Yue Shanshan, Guo Yuxuan, Han Jing-Yan, Wang Huan (2023) Pharmacol Res

Abstract: Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including myocardial infarction and heart failure. These cardiac defects can be mediated by alternative splicing of genes critical for heart function. Whether alternative splicing plays a role in sorafenib-induced cardiotoxicity remains unclear. Transcriptome of rat hearts or human cardiomyocytes treated with sorafenib was analyzed and validated to define alternatively spliced genes and their impact on cardiotoxicity. In rats, sorafenib caused severe cardiotoxicity with decreased left ventricular systolic pressure, elongated sarcomere, enlarged mitochondria and decreased ATP. This was associated with alternative splicing of hundreds of genes in the hearts, many of which were targets of a cardiac specific splicing factor, RBM20. Sorafenib inhibited RBM20 expression in both rat hearts and human cardiomyocytes. The splicing of RBM20's targets, SLC25A3 and FHOD3, was altered into fetal isoforms with decreased function. Upregulation of RBM20 during sorafenib treatment reversed the pathogenic splicing of SLC25A3 and FHOD3, and enhanced the phosphate transport into mitochondria by SLC25A3, ATP synthesis and cell survival.We envision this regulation may happen in many drug-induced cardiotoxicity, and represent a potential druggable pathway for mitigating sorafenib-induced cardiotoxicity. • Keywords: Alternative Splicing, Cardiotoxicity, FHOD3, RBM20, SLC25A3, Sorafenib, Energy metabolism, Sarcomere • Bioblast editor: Plangger M

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

HRR: Oxygraph-2k 

2023-11