2. Academic Validation
  3. USP38 exacerbates myocardial injury and malignant ventricular arrhythmias after ischemia/reperfusion by promoting ferroptosis through the P53/SLC7A11 pathway

USP38 exacerbates myocardial injury and malignant ventricular arrhythmias after ischemia/reperfusion by promoting ferroptosis through the P53/SLC7A11 pathway

  • Int Immunopharmacol. 2025 Jan 3:145:113727. doi: 10.1016/j.intimp.2024.113727.
Yang Gong 1,  Hongjie Yang 1,  Tao Chen 1,  Jingjing Zhang 1,  Bin Kong 1,  Wei Shuai 2,  He Huang 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China.
  • 2 Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China. Electronic address: sw09120@whu.edu.cn.
  • 3 Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China. Electronic address: huanghe1977@whu.edu.cn.
PMID: 39642563 DOI: 10.1016/j.intimp.2024.113727
Abstract

Introduction: Myocardial ischemia-reperfusion (I/R) leads to myocardial injury and malignant ventricular arrhythmias (VAs). Ferroptosis is a novel form of cell death that plays a role in myocardial injury after I/R. Ubiquitin-Specific Protease 38 (USP38), a member of the deubiquitinating Enzyme family, is involved in regulating the progression of inflammation and tumors, but its role in myocardial I/R and Ferroptosis is unclear.

Objectives: Herein, we explored whether USP38 regulates myocardial I/R-induced Ferroptosis and the development of malignant arrhythmias and underlying mechanisms.

Methods: In this study, cardiac I/R mice model was established by ligating/loosening the left anterior descending artery, and the effects of USP38 on I/R-induced Ferroptosis and VAs susceptibility were investigated using USP38 cardiac conditional knockout (USP38-CKO) mice and USP38 cardiac specific overexpression (USP38-TG) mice. In addition, an in vitro I/R model was constructed by hypoxia/reoxygenation (H/R) for further validation.

Results: Our study showed that USP38 expression was significantly increased after I/R. USP38-CKO significantly inhibited I/R-induced iron overload, ROS production, and lipid peroxidation. In addition, USP38-CKO ameliorates post-I/R electrophysiologic abnormalities and reduces susceptibility to VAs. USP38-TG showed the opposite effect, exacerbating Ferroptosis and increasing susceptibility to VAs after I/R. In vivo experiments similarly demonstrated that USP38 significantly exacerbated H/R-induced Ferroptosis. Mechanistically, USP38 directly interacts with P53 and regulates the ubiquitination level of P53 and downstream SLC7A11 expression.

Conclusion: We found that Ferroptosis was significantly associated with VAs after I/R. USP38 can modulate myocardial injury and VAs susceptibility by affecting Ferroptosis, which may be related to the P53/SLC7A11 pathway.

Keywords

Ferroptosis; Ischemia/reperfusion; Ubiquitin-specific protease38; Ventricular arrythmia.

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