SIRT3 attenuates doxorubicin-induced cardiotoxicity by inhibiting NLRP3 inflammasome via autophagy

Abstract

Doxorubicin (DOX) is a highly effective and extensively used chemotherapeutic drug but is limited by its cardiotoxicity. In our previous study, we showed that DOX-induced cardiotoxicity (DIC) triggers autophagy and pyroptosis. Sirtuin 3(SIRT3) is an NAD + -dependent deacetylase of the mitochondria that regulates autophagy. However, it is unknown if the protective effects of SIRT3 on DOX-induced cardiotoxicity involve the inhibition of NLRP3 inflammasome activation. In this study, we constructed in vivo and in vitro DIC models to investigate the effects and potential mechanisms of SIRT3 on DIC. We found that the overexpression of SIRT3 remarkably attenuated DIC through inhibition of the NLRP3 inflammasome. Moreover, we found that the overexpression of SIRT3 restored the dynamic balance of autophagosome/autolysosomes by targeting the mTOR/ULK1 signaling pathway. Application of the mTOR agonist MHY1485 further demonstrated that SIRT3 inhibited NLRP3 inflammasome activation by regulating autophagy. Collectively, the results suggest that SIRT3 effectively attenuates the cardiotoxicity of DOX and provides a theoretical foundation for further exploration of DIC.

Keywords: Autophagy; Cardiotoxicity; Doxorubicin; NLRP3 Inflammasome; SIRT3.