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

  • Nat Commun. 2026 Apr 15. doi: 10.1038/s41467-026-71843-9.
Yixin Zhang  #  1  2  3 ,  Weirun Li  #  1  2 ,  Yingxian Xiao  1  2 ,  Li Luo  1  4 ,  Jiacong Ai  1  2 ,  Shushan Mo  1  3 ,  Lanya Li  1  4 ,  Junyao Deng  1  2 ,  Xueyi Wang  1  3  4 ,  Qishan Li  1  2 ,  Yan Zeng  1  2 ,  Huifang Liu  5 ,  Fei Wang  6  7 ,  Zhenhua Li  8  9  10
Affiliations
  • 1. The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong, China.
  • 2. Shenzhen Clinical Medical School, Southern Medical University, Shenzhen, Guangdong, China.
  • 3. College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China.
  • 4. Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, China.
  • 5. College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, China. [email protected].
  • 6. The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong, China. [email protected].
  • 7. Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, China. [email protected].
  • 8. The Tenth Affiliated Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong, China. [email protected].
  • 9. Shenzhen Clinical Medical School, Southern Medical University, Shenzhen, Guangdong, China. [email protected].
  • 10. Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41986333 DOI: 10.1038/s41467-026-71843-9
Abstract

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.

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