心力衰竭是癌症患者在多柔比星（DOX）治疗中的一个主要副作用。然而，DOX诱导的心力衰竭的机制仍未完全阐明。本研究旨在测试丝氨酸/苏氨酸激酶MST1，作为Hippo通路重要组分，是否参与DOX诱导的心肌损伤的发展。C57BL/6J WT小鼠和具有心肌细胞特异性激酶缺失MST1（激酶失效）过表达的小鼠接受三次每周注射DOX治疗，最终累积剂量达到18mg/kg。在第一次DOX给药后的六周进行了超声心动图、组织学和生化分析。还在体外测试了MST1抑制对DOX诱导的心肌细胞损伤的影响。MST1信号在体外和体内心肌细胞对DOX治疗的反应中显著激活。DOX治疗导致WT小鼠心脏功能障碍和线粒体异常的发生。然而，心肌细胞特异性过表达激酶缺失MST1（DN-MST1）的小鼠或接受XMU-MP-1，一种特异性MST1抑制剂的处理后，这些不良效应被消除，表明MST1抑制剂可减轻DOX引起的心脏功能障碍。DOX治疗导致WT小鼠心脏SIRT3水平显著下调，而MST1抑制剂可恢复这一下调，SIRT3是一种参与线粒体保护的去乙酰化酶。SIRT3的药理学抑制剂削弱了MST1抑制剂的保护作用，表明SIRT3下调介导了MST1激活对DOX治疗的细胞毒性效应。最后，在经过DOX治疗的癌症患者心肌组织中，我们发现MST1的显著上调和SIRT3水平的显著下调。综上所述，MST1通过SIRT3下调对DOX诱导的心肌病的发展发挥作用。© 2023. 作者。

Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.© 2023. The Author(s).