Zhang Zhiming, Jin Binwei, Zhang Yang, Yang Minjun, Wang Cheng, Zhu Yu, Li Tao, Lin Jiangbo, Yang Mengqi, Cheng Ying, Xu Shasha, He Kui, Xu Jiayi, Mi Yafei, Jiang Jianjun, Sun Zhenzhu
Department of Cardiology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Street, Linhai, Zhejiang Province, 317000, China; Laboratory of Cardiovascular Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Street, Linhai, Zhejiang Province, 317000, China.
Laboratory of Cardiovascular Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, No.150 Ximen Street, Linhai, Zhejiang Province, 317000, China; Department of Cardiology, Taizhou Hospital of Zhejiang Province, Shaoxing University, No.150 Ximen Street, Linhai, Zhejiang Province, 317000, China.
Free Radic Biol Med. 2024 Nov 20;225:741-757. doi: 10.1016/j.freeradbiomed.2024.10.302. Epub 2024 Oct 28.
This study investigates the role of the deubiquitinating enzyme USP14 in alleviating doxorubicin (DOX)-induced cardiotoxicity (DIC), particularly concerning its mechanism of regulating pyroptosis through the stabilization of the mitochondrial protein SIRT3. Using in vivo and in vitro models, the research demonstrated that USP14 overexpression protects against DOX-induced cardiac damage by modulating pyroptosis. Silencing SIRT3 via siRNA revealed that SIRT3 is a key intermediary molecule in USP14-mediated regulation of pyroptosis. Notably, DOX exposure resulted in decreased USP14 expression, while its overexpression preserved mitochondrial function and reduced oxidative stress by stabilizing SIRT3. Immunoprecipitation confirmed that USP14 stabilizes SIRT3 through deubiquitination. These findings position USP14 as a promising therapeutic target for mitigating DOX-induced cardiotoxicity by stabilizing SIRT3 and maintaining mitochondrial integrity, suggesting potential novel strategies for cardio-protection in chemotherapy.
本研究调查去泛素化酶USP14在减轻阿霉素（DOX）诱导的心脏毒性（DIC）中的作用，特别是其通过稳定线粒体蛋白SIRT3来调节细胞焦亡的机制。通过体内和体外模型，研究表明USP14过表达通过调节细胞焦亡来保护心脏免受DOX诱导的损伤。通过siRNA沉默SIRT3表明，SIRT3是USP14介导的细胞焦亡调节中的关键中间分子。值得注意的是，DOX暴露导致USP14表达降低，而其过表达通过稳定SIRT3来维持线粒体功能并减少氧化应激。免疫沉淀证实USP14通过去泛素化作用稳定SIRT3。这些发现表明，USP14有望成为通过稳定SIRT3和维持线粒体完整性来减轻DOX诱导的心脏毒性的治疗靶点，为化疗中的心脏保护提供了潜在的新策略。
