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Excessive autophagic degradation of MYLK3 causes sunitinib-induced cardiotoxicity

Ziwei Pan1,2,3,4, Lujie Zhu1,2, Xiaochen Wang3,4

  • 1Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.

Autophagy
|June 26, 2025
PubMed

Insights

Sunitinib causes heart problems by degrading MYLK3, disrupting calcium handling and leading to arrhythmia. Restoring MYLK3 or using omecamtiv mecarbil protects against sunitinib-induced cardiotoxicity.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Sunitinib, a tyrosine kinase inhibitor, treats renal cell carcinoma and gastrointestinal stromal tumors.
  • Clinical use of sunitinib is limited by cardiotoxicity, including reduced cardiac function and heart failure.
  • Molecular mechanisms of sunitinib-induced arrhythmia remain unclear.

Purpose of the Study:

  • Investigate the molecular mechanisms of sunitinib-induced cardiotoxicity.
  • Identify potential therapeutic targets to prevent sunitinib-induced cardiac dysfunction.

Main Methods:

  • Utilized human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to model sunitinib effects.
  • Analyzed sunitinib-induced changes in cardiomyocyte function, calcium transients, and autophagy.
  • Investigated the interaction between SQSTM1/p62 and MYLK3 in sunitinib-treated iPSC-CMs.
  • Assessed the impact of MYLK3 expression and omecamtiv mecarbil (OM) treatment on sunitinib cardiotoxicity.
  • Evaluated the efficacy of nanoparticle-delivered OM in a mouse model of sunitinib-induced cardiac dysfunction.

Main Results:

  • Sunitinib induced cardiomyocyte death, sarcomeric disorganization, irregular Ca2+ transients, and impaired ATP2A2a/SERCA2a activity.
  • Sunitinib treatment led to excessive autophagy and degradation of MYLK3 via SQSTM1/p62 interaction.
  • Downregulation of MYLK3 suppressed CAMK2-PLN signaling, impairing ATP2A2a/SERCA2a activity and causing Ca2+ dyshomeostasis and arrhythmia.
  • Overexpression of MYLK3 or treatment with omecamtiv mecarbil reversed sunitinib-induced pathogenic phenotypes.
  • Nanoparticle delivery of OM prevented sunitinib-induced cardiac dysfunction in mice.

Conclusions:

  • Sunitinib-induced MYLK3 degradation inhibits the CAMK2-PLN-ATP2A2a pathway, leading to arrhythmogenesis.
  • MYLK3 is a novel cardioprotective target for mitigating sunitinib-induced cardiotoxicity.
  • Pharmacological targeting of MYLK3 or its downstream pathways may offer a strategy to prevent sunitinib cardiotoxicity.
Keywords:
ArrhythmiaMYLK3autophagyiPSC-derived cardiomyocytessunitinib-induced cardiotoxicity

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