2. Academic Validation
  3. USP14 modulates cell pyroptosis and ameliorates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing SIRT3

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

  • Free Radic Biol Med. 2024 Nov 20:225:741-757. doi: 10.1016/j.freeradbiomed.2024.10.302.
Zhiming Zhang 1,  Binwei Jin 1,  Yang Zhang 1,  Minjun Yang 1,  Cheng Wang 2,  Yu Zhu 3,  Tao Li 1,  Jiangbo Lin 1,  Mengqi Yang 1,  Ying Cheng 1,  Shasha Xu 1,  Kui He 1,  Jiayi Xu 2,  Yafei Mi 4,  Jianjun Jiang 5,  Zhenzhu Sun 6
Affiliations

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.

Figures
Products
Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15534
    99.0%, Mitochondrial Membrane Potential Probe
Other Products