4.7 Article

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

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ENVIRONMENTAL TOXICOLOGY
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WILEY
DOI: 10.1002/tox.24075

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bardoxolone methyl; cardiotoxicity; doxorubicin; pyroptosis

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This study reveals the specific mechanism by which bardoxolone methyl alleviates doxorubicin-induced cardiotoxicity by activating the Nrf2 pathway and inhibiting the TXNIP-NLRP3 pathway. Bardoxolone methyl reduces oxidative stress and pyroptosis, thereby alleviating myocardial damage and cardiac fibrosis.
Bardoxolone methyl, which triggers nuclear factor erythroid 2-related factor (Nrf2), has therapeutic effects against myocardial infarction, heart failure, and other diseases. Nrf2 can inhibit the activation of the thioredoxin-interacting protein (TXNIP)/NLR family pyrin domain-containing protein 3 (NLRP3) pathway. Doxorubicin is an anthracycline chemotherapeutic drug associated with cardiotoxicity, limiting its clinical use. In this study, we explored the specific mechanism of the Nrf2-TXNIP-NLRP3 pathway in doxorubicin-induced cardiotoxicity using bardoxolone methyl in animal and cell models. Using in vivo and in vitro experiments, we show that doxorubicin can induce oxidative stress and pyroptosis in the heart. Western blot and co-immunoprecipitation experimental results found that doxorubicin can reduce the interaction between TXNIP and TRX, increase the interaction between TXNIP and NLRP3, and activate the pyroptosis process. Bardoxolone methyl reduces the accumulation of reactive oxygen species in cardiomyocytes through the Nrf2 pathway, inhibits the interaction between TXNIP and NLRP3, and alleviates the progression of myocardial damage and cardiac fibrosis. Bardoxolone methyl lost its therapeutic effect when the expression of Nrf2 was decreased. Additionally, repressing the expression of TXNIP can inhibit the activation of NLRP3 and alleviate myocardial damage caused by doxorubicin. Collectively, our findings confirm that bardoxolone methyl alleviates doxorubicin-induced cardiotoxicity by activating Nrf2 and inhibiting the TXNIP-NLRP3 pathway.

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