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

Background: 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.

Objective: 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.

Conclusions: 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.