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<p>Doxorubicin-induced cardiotoxicity represents a significant clinical adverse effect associated with cancer chemotherapy treatment. Inspired by cancer drug resistance mechanisms, we propose a novel strategy termed transient overexpression of p-glycoprotein for cardiac reprogramming to induce cardiac drug resistance as a treatment for cardiotoxicity. This approach involves reprogramming cardiomyocytes by delivering lipid nanoparticles-based mRNA therapeutics to induce temporary p-glycoprotein overexpression, which in turn reduces intracellular doxorubicin levels and suppresses cytotoxic effects. This strategy results in promoted p-glycoprotein overexpression in cardiomyocytes, improved survival rates, restored cardiac function, and reduced myocardial fibrosis and structural cardiac alterations in a mouse model with doxorubicin-induced cardiotoxicity. Furthermore, studies in large animals show that intrapericardial injection of lipid nanoparticles with p-glycoprotein mRNAs effectively mitigates adverse effects and restores cardiac function in male pig models of doxorubicin-induced cardiotoxicity. The significant cardioprotective effects achieved through cardiac drug resistance highlight the safety, efficacy, and clinical potential of this strategy for alleviating doxorubicin-induced cardiotoxicity.</p>

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Cardiac reprogramming via transient overexpression of P-glycoprotein alleviates doxorubicin-induced cardiotoxicity in mice and pigs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Yixin Zhang,
  • Weirun Li,
  • Yingxian Xiao,
  • Li Luo,
  • Jiacong Ai,
  • Shushan Mo,
  • Lanya Li,
  • Junyao Deng,
  • Xueyi Wang,
  • Qishan Li,
  • Yan Zeng,
  • Huifang Liu,
  • Fei Wang,
  • Zhenhua Li

摘要

Doxorubicin-induced cardiotoxicity represents a significant clinical adverse effect associated with cancer chemotherapy treatment. Inspired by cancer drug resistance mechanisms, we propose a novel strategy termed transient overexpression of p-glycoprotein for cardiac reprogramming to induce cardiac drug resistance as a treatment for cardiotoxicity. This approach involves reprogramming cardiomyocytes by delivering lipid nanoparticles-based mRNA therapeutics to induce temporary p-glycoprotein overexpression, which in turn reduces intracellular doxorubicin levels and suppresses cytotoxic effects. This strategy results in promoted p-glycoprotein overexpression in cardiomyocytes, improved survival rates, restored cardiac function, and reduced myocardial fibrosis and structural cardiac alterations in a mouse model with doxorubicin-induced cardiotoxicity. Furthermore, studies in large animals show that intrapericardial injection of lipid nanoparticles with p-glycoprotein mRNAs effectively mitigates adverse effects and restores cardiac function in male pig models of doxorubicin-induced cardiotoxicity. The significant cardioprotective effects achieved through cardiac drug resistance highlight the safety, efficacy, and clinical potential of this strategy for alleviating doxorubicin-induced cardiotoxicity.