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...
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202301852 |
| _version_ | 1827797387078270976 |
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| author | Lulu Liu Jiaojiao Pang Dandan Qin Ruochuan Li Dan Zou Kai Chi Wenxiao Wu Haiying Rui Huaxiang Yu Wenyong Zhu Kai Liu Xuting Wu Jinxin Wang Ping Xu Xiaoshuai Song Yihai Cao Jiali Wang Feng Xu Li Xue Yuguo Chen |
| author_facet | Lulu Liu Jiaojiao Pang Dandan Qin Ruochuan Li Dan Zou Kai Chi Wenxiao Wu Haiying Rui Huaxiang Yu Wenyong Zhu Kai Liu Xuting Wu Jinxin Wang Ping Xu Xiaoshuai Song Yihai Cao Jiali Wang Feng Xu Li Xue Yuguo Chen |
| author_sort | Lulu Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T19:22:23Z |
| format | Article |
| id | doaj.art-bf70f1bc9a674fac9a170ff5b88f44e6 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-11T19:22:23Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-bf70f1bc9a674fac9a170ff5b88f44e62023-10-07T03:51:50ZengWileyAdvanced Science2198-38442023-10-011028n/an/a10.1002/advs.202301852Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion InjuryLulu Liu0Jiaojiao Pang1Dandan Qin2Ruochuan Li3Dan Zou4Kai Chi5Wenxiao Wu6Haiying Rui7Huaxiang Yu8Wenyong Zhu9Kai Liu10Xuting Wu11Jinxin Wang12Ping Xu13Xiaoshuai Song14Yihai Cao15Jiali Wang16Feng Xu17Li Xue18Yuguo Chen19Department of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Thoracic Surgery Qilu Hospital of Shandong University Qingdao 266035 ChinaDepartment of Cardiovascular surgery Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Microbiology Tumor and Cell Biology Karolinska Institute Stockholm 171 65 SwedenDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaDepartment of Emergency Medicine Qilu Hospital of Shandong University Jinan 250012 ChinaAbstract 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.https://doi.org/10.1002/advs.2023018524‐hydroxy‐2‐nonenal (4‐HNE)ferroptosisglutathione peroxidase 4 (GPX4)myocardial ischemia reperfusion injuryovarian tumor (OTU) deubiquitinase 5 (OTUD5) |
| spellingShingle | Lulu Liu Jiaojiao Pang Dandan Qin Ruochuan Li Dan Zou Kai Chi Wenxiao Wu Haiying Rui Huaxiang Yu Wenyong Zhu Kai Liu Xuting Wu Jinxin Wang Ping Xu Xiaoshuai Song Yihai Cao Jiali Wang Feng Xu Li Xue Yuguo Chen Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury Advanced Science 4‐hydroxy‐2‐nonenal (4‐HNE) ferroptosis glutathione peroxidase 4 (GPX4) myocardial ischemia reperfusion injury ovarian tumor (OTU) deubiquitinase 5 (OTUD5) |
| title | Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury |
| title_full | Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury |
| title_fullStr | Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury |
| title_full_unstemmed | Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury |
| title_short | Deubiquitinase OTUD5 as a Novel Protector against 4‐HNE‐Triggered Ferroptosis in Myocardial Ischemia/Reperfusion Injury |
| title_sort | deubiquitinase otud5 as a novel protector against 4 hne triggered ferroptosis in myocardial ischemia reperfusion injury |
| topic | 4‐hydroxy‐2‐nonenal (4‐HNE) ferroptosis glutathione peroxidase 4 (GPX4) myocardial ischemia reperfusion injury ovarian tumor (OTU) deubiquitinase 5 (OTUD5) |
| url | https://doi.org/10.1002/advs.202301852 |
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