Deubiquitinase OTUD5 as a Novel Protector against 4-HNE-Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury

Despite the development of advanced technologies for interventional coronary reperfusion after myocardial infarction, a substantial number of patients experience high mortality due to myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury can provide crucial strategies for mitigating myocardial damage and improving patient survival. Here, it is discovered that the 4-hydroxy-2-nonenal (4-HNE) accumulates during MI/R, accompanied by high rates of myocardial ferroptosis. The loss-of-function of aldehyde dehydrogenase 2 (ALDH2), which dissipates 4-HNE, aggravates myocardial ferroptosis, whereas the activation of ALDH2 mitigates ferroptosis. Mechanistically, 4-HNE targets glutathione peroxidase 4 (GPX4) for K48-linked polyubiquitin-related degradation, which 4-HNE-GPX4 axis commits to myocyte ferroptosis and forms a positive feedback circuit. 4-HNE blocks the interaction between GPX4 and ovarian tumor (OTU) deubiquitinase 5 (OTUD5) by directly carbonylating their cysteine residues at C93 of GPX4 and C247 of OTUD5, identifying OTUD5 as the novel deubiquitinase for GPX4. Consequently, the elevation of OTUD5 deubiquitinates and stabilizes GPX4 to reverse 4-HNE-induced ferroptosis and alleviate MI/R injury. The data unravel the mechanism of 4-HNE in GPX4-dependent ferroptosis and identify OTUD5 as a novel therapeutic target for the treatment of MI/R injury.

Automated summary

Despite advances in interventional coronary reperfusion, myocardial ischemia-reperfusion (MI/R) injury remains a major cause of high mortality. This study reveals that during MI/R, 4-hydroxy-2-nonenal (4-HNE) accumulates and leads to myocardial ferroptosis. Loss of function of aldehyde dehydrogenase 2 (ALDH2) worsens ferroptosis, while activation of ALDH2 mitigates it. Mechanistically, 4-HNE targets glutathione peroxidase 4 (GPX4) for degradation and forms a positive feedback loop, contributing to myocyte ferroptosis. Furthermore, 4-HNE carbonylates cysteine residues of GPX4 and OTU deubiquitinase 5 (OTUD5), preventing their interaction and identifying OTUD5 as a novel deubiquitinase for GPX4. Elevated OTUD5 deubiquitinates and stabilizes GPX4, reversing 4-HNE-induced ferroptosis and alleviating MI/R injury. These findings provide insights into the mechanisms of 4-HNE in GPX4-dependent ferroptosis and identify OTUD5 as a potential therapeutic target for MI/R injury.