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

Abstract

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.

Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

“…This cycle of lipid peroxidation and 4-HNE formation contributes to increased oxidative stress within the cell, ultimately driving ferroptotic cell death . 4-HNE can inhibit the activity of downstream effectors GPX4, a key enzyme that detoxifies lipid hydroperoxides . GPX4 inhibition by 4-HNE reduces the cell’s ability to combat lipid peroxidation, facilitating the progression of ferroptosis.…”

“… 76 4-HNE can inhibit the activity of downstream effectors GPX4, a key enzyme that detoxifies lipid hydroperoxides. 77 GPX4 inhibition by 4-HNE reduces the cell’s ability to combat lipid peroxidation, facilitating the progression of ferroptosis. 4-HNE also showed an upregulation in the cells treated with miRNA34a and cocultured with inactive or active Jurkat T cells ( Figure 8 ).…”

The role of deubiquitinases in cardiac disease

“…OTUD5 inhibited ferroptosis and alleviated myocardial injury by directly binding to glutathione peroxidase 4 (GPX4), the key protein of ferroptosis, and removing the K48-linked ubiquitin chains of GPX4 (Ref. 82 ).…”

Ferroptosis in liver cancer: a key role of post-translational modifications

“…The interaction between Transmembrane member 16A (TMEM16A) and GPX4 leads to the ubiquitination and degradation of GPX4, thereby promoting ferroptosis ( 115 ). The presence of 4-HNE facilitates the carbonylation modification of cysteine residue 93 in GPX4, thereby attenuating the interaction between ovarian tumor (OTU) deubiquitinase 5 (OTUD5) and GPX4, and promoting the ubiquitination-mediated degradation of GPX4 ( 116 ).…”