核去乙酰化酶Sirt6与能量代谢调节和抗氧化应激关系密切。阿霉素（DOX）造成心肌毒性的最基本机制是诱导强烈的氧化应激和细胞死亡。DOX诱导心肌p53大量增加，p53在DOX心肌损伤中起关键和复杂的调节作用。我们拟在Sirt6拮抗氧化应激缓解心脏急性心梗研究的基础上，构建Sirt6+/-小鼠腹腔注射DOX诱导的心脏损伤模型及离体培养的Sirt6沉默和过表达的心肌细胞DOX损伤模型，探讨Sirt6拮抗DOX心肌病的保护作用，利用IP/coIP、EMSA及ChIP等实验技术研究Sirt6与p53的相互作用，阐明p53招募Sirt6至其下游促氧化应激基因脯氨酸氧化酶和促细胞死亡基因Fas的启动子区，减低H3K9的乙酰化状态，抑制这些基因的转录表达，缓解氧化应激反应和细胞死亡，拮抗DOX心脏毒性的内源性保护作用和创新性负性调控机制，为DOX心脏毒性防治和肿瘤心脏病学研究提供新治疗策略和理论依据。

Sirt6, a NAD+-dependent nuclear Histone deacetylase, is closely related to energy metabolism regulation and antioxidant stress. Doxorubicin (DOX) leads to cardiotoxicity through the induction of excessive oxidative stress and cell death, which are the crucial mechanisms for DOX injury in hearts. DOX induces a large increase in p53 levels in cardiomyocytes, which play an essential and complex role in the regulation of DOX-induced cardiotoxicity. We have reported that Sirt6 protected hearts against the acute infarction injury by suppressing the excessive oxidative stress. Here, we propose to reveal a new protection of Sirt6 against DOX cardiotoxicity by using an in vivo model induced by the intraperitoneal injection of DOX in Sirt6+/- and WT mice, as well as a DOX-treated cell model in primary cultured neonatal rat cardiomyocytes (NRCMs) with Sirt6 gene silence or overexpression. We further explore the interaction between Sirt6 and p53 in cardiomyocytes by using IP/coIP, EMSA and ChIP experiments, to reveal how p53 recruits Sirt6 to the promoter regions of its downstream pro-oxidative stress proline oxidase and pro-cell death gene Fas, and then reducing H3K9 acetylation levels to suppress the transcription and expression of both proline oxidase and Fas. Furthermore, Sirt6 protects hearts from DOX-induced cardiotoxicity by alleviating oxidative stress injury and cardiomyocyte death. Our study reveals an endogenous protection and innovative negative regulation of Sirt6 on DOX-induced cardiotoxicity, which will provides a new therapeutic strategy for the treatment of DOX-induced cardiomyopathy and offers new findings for oncocardiology.