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Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes

Songming Liu1, Shanshan Yue2, Yuxuan Guo3

  • 1Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.

Pharmacological Research
|November 25, 2023
PubMed

Insights

Sorafenib causes heart damage by altering gene splicing, specifically affecting the RBM20 protein. Restoring RBM20 levels can reverse these harmful effects, offering a potential treatment for drug-induced cardiotoxicity.

Area of Science:

  • Cardiovascular Research
  • Molecular Biology
  • Pharmacology

Background:

  • Sorafenib, a tyrosine kinase inhibitor, treats advanced solid tumors but causes cardiotoxicity.
  • Cardiotoxicity may involve alternative gene splicing critical for heart function.
  • The role of alternative splicing in sorafenib-induced cardiotoxicity is not fully understood.

Purpose of the Study:

  • To investigate the role of alternative splicing in sorafenib-induced cardiotoxicity.
  • To identify specific genes and pathways affected by sorafenib treatment.
  • To explore RBM20 as a potential therapeutic target.

Main Methods:

  • Transcriptome analysis of rat hearts and human cardiomyocytes treated with sorafenib.
  • Validation of alternatively spliced genes and their functional impact.
  • Assessment of RBM20 expression and its targets (SLC25A3, FHOD3) under sorafenib treatment.

Main Results:

  • Sorafenib induced severe cardiotoxicity in rats, affecting cardiac function and mitochondrial ATP production.
  • Hundreds of genes, including RBM20 targets, exhibited altered splicing patterns.
  • Sorafenib inhibited RBM20 expression, leading to pathogenic splicing of SLC25A3 and FHOD3 into less functional fetal isoforms.
  • Upregulating RBM20 reversed these splicing defects, improving mitochondrial function and cell survival.

Conclusions:

  • Alternative splicing, mediated by RBM20 dysregulation, is a key mechanism in sorafenib-induced cardiotoxicity.
  • Targeting RBM20 offers a potential therapeutic strategy to mitigate sorafenib cardiotoxicity.
  • This RBM20-dependent pathway may be relevant for other drug-induced cardiotoxicities.
Keywords:
Alternative SplicingCardiotoxicityEnergy metabolismFHOD3RBM20SLC25A3SarcomereSorafenib

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