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Bardoxolone methyl attenuates doxorubicin-induced cardiotoxicity by inhibiting the TXNIP-NLRP3 pathway through Nrf2

Wei Zhang1, Chao Shi2, Zhuoya Yao1

  • 1Department of Cardiovascular Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China.

Environmental Toxicology
|December 8, 2023
PubMed

Insights

Bardoxolone methyl protects the heart from doxorubicin damage by activating the Nrf2 pathway. This inhibits the TXNIP/NLRP3 pathway, reducing oxidative stress and pyroptosis, thus preventing cardiotoxicity.

Area of Science:

  • Cardiology
  • Pharmacology
  • Molecular Biology

Background:

  • Doxorubicin chemotherapy causes cardiotoxicity, limiting its use.
  • Bardoxolone methyl activates nuclear factor erythroid 2-related factor (Nrf2), a pathway with therapeutic potential.
  • Nrf2 can inhibit the thioredoxin-interacting protein (TXNIP)/NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome pathway.

Purpose of the Study:

  • To investigate the mechanism of the Nrf2-TXNIP-NLRP3 pathway in doxorubicin-induced cardiotoxicity.
  • To evaluate the therapeutic effect of bardoxolone methyl on doxorubicin cardiotoxicity in preclinical models.

Main Methods:

  • In vivo and in vitro experiments using animal and cell models.
  • Western blot and co-immunoprecipitation assays to analyze protein interactions.
  • Assessment of oxidative stress, pyroptosis, myocardial damage, and cardiac fibrosis.

Main Results:

  • Doxorubicin induced oxidative stress and pyroptosis in cardiomyocytes.
  • Doxorubicin disrupted TXNIP-TRX interaction, promoting TXNIP-NLRP3 interaction and pyroptosis.
  • Bardoxolone methyl, via Nrf2 activation, reduced reactive oxygen species, inhibited TXNIP-NLRP3 interaction, and alleviated myocardial damage and fibrosis.
  • Therapeutic effects of bardoxolone methyl were abolished by Nrf2 downregulation.
  • Repressing TXNIP expression ameliorated doxorubicin-induced cardiotoxicity.

Conclusions:

  • Bardoxolone methyl alleviates doxorubicin-induced cardiotoxicity by activating Nrf2.
  • Inhibition of the TXNIP-NLRP3 pathway is a key mechanism for bardoxolone methyl's cardioprotective effects.
  • Targeting the Nrf2-TXNIP-NLRP3 axis offers a potential strategy for managing chemotherapy-induced heart damage.
Keywords:
bardoxolone methylcardiotoxicitydoxorubicinpyroptosis

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