USP14 modulates cell pyroptosis and ameliorates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing SIRT3

Zhiming Zhang; Binwei Jin; Yang Zhang; Minjun Yang; Cheng Wang; Yu Zhu; Tao Li; Jiangbo Lin; Mengqi Yang; Ying Cheng; Shasha Xu; Kui He; Jiayi Xu; Yafei Mi; Jianjun Jiang; Zhenzhu Sun

doi:10.1016/j.freeradbiomed.2024.10.302

USP14 modulates cell pyroptosis and ameliorates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing SIRT3

Free Radic Biol Med. 2024 Oct 28:225:741-757. doi: 10.1016/j.freeradbiomed.2024.10.302. Online ahead of print.

Authors

Zhiming Zhang¹, Binwei Jin¹, Yang Zhang¹, Minjun Yang¹, Cheng Wang², Yu Zhu³, Tao Li¹, Jiangbo Lin¹, Mengqi Yang¹, Ying Cheng¹, Shasha Xu¹, Kui He¹, Jiayi Xu², Yafei Mi⁴, Jianjun Jiang⁵, Zhenzhu Sun⁶

Affiliations

¹ 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.
² 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.
³ Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, No.150 Ximen Street, Linhai, Zhejiang Province, 317000, China.
⁴ 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; Department of Cardiology, Taizhou Hospital of Zhejiang Province, Shaoxing University, No.150 Ximen Street, Linhai, Zhejiang Province, 317000, China. Electronic address: miyf@enzemed.com.
⁵ 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. Electronic address: Jiangjj@enzemed.com.
⁶ 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. Electronic address: sunzz0958@enzemed.com.

PMID: 39490774
DOI: 10.1016/j.freeradbiomed.2024.10.302

Abstract

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.

Keywords: Deubiquitination; Doxorubicin-induced cardiotoxicity; Pyroptosis; SIRT3; USP14.