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

4-hydroxy-2-nonenal (4-HNE) ferroptosis glutathione peroxidase 4 (GPX4) myocardial ischemia reperfusion injury ovarian tumor (OTU) deubiquitinase 5 (OTUD5)

Journal

Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569

Informations de publication

Date de publication:
Oct 2023
Historique:
revised: 13 07 2023
received: 21 03 2023
pubmed: 8 8 2023
medline: 8 8 2023
entrez: 8 8 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1002/advs.202301852 PMID: 37552043 PMC: PMC10558642
pubmed: 37552043
doi: 10.1002/advs.202301852
pmc: PMC10558642
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2301852

Subventions

Organisme : State Key Program of the National Natural Science Foundation of China
ID : 82030059
Organisme : National Natural Science Foundation of China
ID : 82172178
Organisme : National Natural Science Foundation of China
ID : 82072144
Organisme : National Natural Science Foundation of China
ID : 81873950
Organisme : National Natural Science Foundation of China
ID : 81873953
Organisme : National Natural Science Foundation of China
ID : 81300219
Organisme : National Natural Science Foundation of China
ID : 81671951
Organisme : National Key R&D Program of China
ID : 2020YFC1512700
Organisme : National Key R&D Program of China
ID : 2020YFC1512705
Organisme : National Key R&D Program of China
ID : 2020YFC1512703
Organisme : National S&T Fundamental Resources Investigation Project
ID : 2018FY100600
Organisme : National S&T Fundamental Resources Investigation Project
ID : 2018FY100602
Organisme : Key R&D Program of Shandong Province
ID : 2021ZLGX02
Organisme : Key R&D Program of Shandong Province
ID : 2022ZLGX03
Organisme : Natural Science Foundation of Shandong Province
ID : ZR2022MH078
Organisme : Key R&D Program of Shandong Province
ID : 2019GSF108131
Organisme : Taishan Young Scholar Program of Shandong Province
ID : tsqn202103173
Organisme : Taishan Pandeng Scholar Program of Shandong Province
ID : tspd20181220
Organisme : Youth Top-Talent Project of National Ten Thousand Talents Plan

Informations de copyright

© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

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Auteurs

Lulu Liu (L)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Jiaojiao Pang (J)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Dandan Qin (D)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Ruochuan Li (R)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Dan Zou (D)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Kai Chi (K)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Wenxiao Wu (W)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Haiying Rui (H)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Huaxiang Yu (H)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Wenyong Zhu (W)

Department of Thoracic Surgery, Qilu Hospital of Shandong University, Qingdao, 266035, China.

Kai Liu (K)

Department of Cardiovascular surgery, Qilu Hospital of Shandong University, Jinan, 250012, China.

Xuting Wu (X)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Jinxin Wang (J)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Ping Xu (P)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Xiaoshuai Song (X)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Yihai Cao (Y)

Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, 171 65, Sweden.

Jiali Wang (J)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Feng Xu (F)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.
ORCID: 0000-0002-4670-3727

Li Xue (L)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.
ORCID: 0000-0002-1004-9225

Yuguo Chen (Y)

Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China.
Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China.
NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China.

Classifications MeSH