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Updated: Sep 20, 2025

A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
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Cardiomyocyte-localized CCDC25 senses NET DNA to promote doxorubicin cardiotoxicity by activating autophagic flux

Man Nie1, Dexin Lei2, Zhou Liu3,4

  • 1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. nieman@sysucc.org.cn.

Nature Cancer
|May 29, 2025
PubMed

Insights

Anthracycline chemotherapy causes heart damage. This study reveals neutrophil extracellular traps (NETs) and CCDC25 protein mediate this cardiotoxicity, offering a potential dual-action therapeutic target.

Area of Science:

  • Cardiology
  • Oncology
  • Immunology

Background:

  • Cardiotoxicity limits anthracycline use in cancer treatment.
  • The role of extracellular DNA in cardiotoxicity is not well understood.

Purpose of the Study:

  • To investigate the role of neutrophil extracellular traps (NETs) and extracellular DNA in anthracycline-induced cardiotoxicity.
  • To explore CCDC25 as a potential therapeutic target for mitigating cardiotoxicity.

Main Methods:

  • Analysis of circulating NET DNA in lymphoma patients undergoing anthracycline treatment.
  • Mouse models and human myocardial slices to study doxorubicin-induced cardiac NET formation.
  • Investigated the interaction between NET DNA and cardiomyocyte CCDC25.

Main Results:

  • Elevated circulating NET DNA observed in patients with cardiotoxicity.
  • Doxorubicin induces HMGB1-dependent cardiac NET formation, leading to cardiac remodeling and dysfunction.
  • CCDC25 on cardiomyocytes recognizes NET DNA, generating reactive oxygen species and activating autophagic flux, impairing cardiac function.

Conclusions:

  • NETs and CCDC25 play a significant role in anthracycline cardiotoxicity.
  • Targeting CCDC25 alleviates cardiotoxicity and enhances doxorubicin's antitumor effects in preclinical models.
  • CCDC25 inhibition offers a potential dual therapeutic and cardioprotective strategy.

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