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The function of PCSK9 in doxorubicin-induced cardiotoxicity and its underlying mechanism

Shuai Shi1,2, Zhihui Qin3, Chang Liu4

  • 1Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. shishuai@hrbmu.edu.cn.

Scientific Reports
|July 2, 2025
PubMed

Insights

Doxorubicin chemotherapy causes heart damage by increasing PCSK9 protein. PCSK9 inhibitors like evolocumab protected against this cardiotoxicity, suggesting a new treatment strategy.

Area of Science:

  • Cardiology
  • Oncology
  • Molecular Biology

Background:

  • Doxorubicin (DOX) chemotherapy is limited by cardiotoxicity.
  • Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is linked to cardiovascular disease.
  • The relationship between PCSK9 and DOX-induced cardiotoxicity (DIC) is unexplored.

Purpose of the Study:

  • To investigate the role of PCSK9 in DOX-induced cardiotoxicity.
  • To explore the therapeutic potential of PCSK9 inhibition against DIC.

Main Methods:

  • DOX was administered to mice to induce cardiotoxicity.
  • PCSK9 expression and its interaction with KPNB1 were analyzed in myocardial tissue and H9C2 cells.
  • Evolocumab, a PCSK9 inhibitor, was used to assess its protective effects.

Main Results:

  • DOX treatment increased PCSK9 expression in the heart.
  • Evolocumab administration improved cardiac function and reduced myocardial injury and fibrosis in DOX-treated mice.
  • PCSK9 inhibition modulated cardiomyocyte apoptosis by affecting Bax/Bcl-2 and Cleaved Caspase-3/Pro Caspase-3 ratios and regulating KPNB1.

Conclusions:

  • PCSK9 plays a significant role in DOX-induced cardiotoxicity.
  • PCSK9 inhibition demonstrates a protective effect against DOX-induced cardiotoxicity.
  • Targeting PCSK9 may represent a novel therapeutic strategy for mitigating chemotherapy-related heart damage.
Keywords:
ApoptosisCardiotoxicityDoxorubicinKPNB1PCSK9

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