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As an effective anticancer drug,the clinical limitation of doxorubicin(Dox)is the time-and dose-dependent cardiotoxicity.Yes-associated protein 1(YAP1)interacts with transcription factor TEA domain 1(TEAD1)and plays an important role in cell proliferation and survival.However,the role of YAP1 in Dox-induced cardiomyopathy has not been reported.In this study,the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model.Ectopic expression of Yap 1 significantly blocked Dox-induced cardiomyo-cytes apoptosis in TEAD1 dependent manner.Isorhapontigenin(Isor)is a new derivative of stilbene and responsible for a wide range of biological processes.Here,we found that Isor effectively relieved Dox-induced cardiomyocytes apoptosis in a dose-dependent manner in vitro.Administration with Isor(30 mg/kg/day,intraperitoneally,3 weeks)significantly protected against Dox-induced cardiotoxicity in mice.Interestingly,Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro.Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity.In conclusion,YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.