Ke Jiaxing, Li Lingjia, Chen Shuling, Liao Chenxin, Peng Feng, Chai Dajun, Lin Jinxiu
The Higher Educational Key Laboratory for Cardiovascular Disease of Fujian Province, Clinical Research Center for Metabolic Heart Disease of Fujian Province, Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Int J Mol Sci. 2025 Aug 23;26(17):8201. doi: 10.3390/ijms26178201.
Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia-reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC.
阿霉素（DOX）是一种蒽环类化疗药物，临床上受阿霉素诱导的心脏毒性（DIC）限制，铁死亡和凋亡被确定为关键机制。作为一种抗氧化酶，GPX4在心肌缺血再灌注损伤期间经历泛素介导的降解；然而，其泛素化在DIC中的作用仍不清楚。本研究表明，GPX4在DIC期间经历泛素化降解，加剧心肌细胞中的铁死亡和凋亡。发现NEDD4L与GPX4相互作用，其表达在DOX处理的小鼠心肌组织和心肌细胞中上调。NEDD4L敲低减轻了DIC以及心肌细胞中的铁死亡和凋亡。机制上，NEDD4L通过其WW结构域识别GPX4，并在DOX刺激下通过其HECT结构域介导GPX4的K48连接的泛素化和降解。NEDD4L敲低降低了DOX诱导的GPX4泛素化水平和随后的降解。值得注意的是，虽然NEDD4L敲低减轻了DOX诱导的细胞死亡，但同时敲低GPX4减弱了这种保护作用，表明GPX4是NEDD4L调节心肌细胞死亡的关键下游靶点。这些发现确定NEDD4L是预防和治疗DIC的潜在治疗靶点。
