Abstract：
Doxorubicin (DOX) is a widely utilized chemotherapeutic agent in clinical oncology for treating various cancers. However, its clinical use is constrained by its significant side effects. Among these, the development of cardiomyopathy, characterized by cardiac remodeling and eventual heart failure, stands as a major concern following DOX chemotherapy. In our current investigation, we have showcased the efficacy of MLN4924 in mitigating doxorubicin-induced cardiotoxicity through direct inhibition of the NEDD8-activating enzyme, NAE. MLN4924 demonstrated the ability to stabilize mitochondrial function post-doxorubicin treatment, diminish cardiomyocyte apoptosis, alleviate oxidative stress-induced damage in the myocardium, enhance cardiac contractile function, mitigate cardiac fibrosis, and impede cardiac remodeling associated with heart failure. At the mechanistic level, MLN4924 intervened in the neddylation process by inhibiting the NEDD8 activating enzyme, NAE, within the murine cardiac tissue subsequent to doxorubicin treatment. This intervention resulted in the suppression of NEDD8 protein expression, reduction in neddylation activity, and consequential manifestation of cardioprotective effects. Collectively, our findings posit MLN4924 as a potential therapeutic avenue for mitigating doxorubicin-induced cardiotoxicity by attenuating heightened neddylation activity through NAE inhibition, thereby offering a viable and promising treatment modality for afflicted patients.
摘要：
阿霉素（Dox）是临床肿瘤学中广泛使用的化学治疗剂，用于治疗各种癌症。然而,其临床应用受到其显著副作用的限制。其中,心肌病的发展，以心脏重塑和最终的心力衰竭为特征，是Dox化疗后的主要问题。在我们目前的调查中，我们展示了MLN4924通过直接抑制NEDD8激活酶减轻阿霉素诱导的心脏毒性的功效，NAE。MLN4924证明了多柔比星治疗后稳定线粒体功能的能力，减少心肌细胞凋亡，减轻氧化应激诱导的心肌损伤，增强心脏收缩功能，减轻心脏纤维化，并阻碍与心力衰竭相关的心脏重塑。在机械层面，MLN4924通过抑制NEDD8激活酶干预了Neddylation过程，NAE,在阿霉素治疗后的鼠心脏组织内。这种干预导致NEDD8蛋白表达的抑制，Neddylation活性降低，以及心脏保护作用的相应表现。总的来说，我们的研究结果认为MLN4924是一种潜在的治疗途径，通过NAE抑制减弱增强的neddylation活性来减轻阿霉素诱导的心脏毒性，从而为患病的患者提供了一种可行且有希望的治疗方式。
