Neuregulin-1 reduces Doxorubicin-induced cardiotoxicity by upregulating YAP to inhibit senescence

Abstract

The cardiotoxicity of Doxorubicin (Dox) limits its clinical application, creating an urgent need to investigate its underlying mechanism and develop effective therapies. Senescence plays an important role in Dox-induced cardiotoxicity (DIC). Recently, Neuregulin-1 (NRG1) was found to regulate Yes-associated protein (YAP), which was reported to inhibit senescence, suggesting that NRG1 might be used to treat DIC by inhibiting senescence through YAP regulation. We examined the changes and regulatory roles of YAP and senescence in Dox cardiotoxicity and whether NRG1 could reduce DIC in chronic DIC mice and Dox-treated H9c2 cells. Our study revealed that sustained small doses of Dox impaired cardiac function and H9c2 cell viability, induced myocardial senescence, and inhibited YAP expression. Conversely, high levels of YAP inhibited Dox-induced senescence in H9c2 cells, indicating that Dox promotes myocardial senescence by inhibiting YAP. In addition, we found that exogenous NRG1 inhibited the phosphorylation of LATS1 and MST1, thereby inhibiting YAP phosphorylation and promote the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. YAP knockdown or inhibition of YAP binding to TEA domain transcription factor protein （TEAD）blocks the protective effects of NRG1. In conclusion, our study suggests that Dox-induced myocardial senescence through YAP inhibition is one of the pathological mechanisms of its cardiotoxicity. Additionally, NRG1 reduces DIC by upregulating YAP to inhibit senescence.