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ABSTRACT Acetaldehyde dehydrogenase 2 (_ALDH2_) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome

(ARDS) remains unknown. Here, we showed that human subjects carrying the _ALDH2__rs671_ mutation were highly susceptible to developing septic ARDS. Intriguingly, _ALDH2__rs671_-ARDS patients

showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than _ALDH2__WT_-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the

development of septic ARDS, we utilized _Aldh2_ gene knockout mice and _Aldh2__rs671_ gene knock-in mice. In clinically relevant mouse sepsis models, _Aldh2_-/- mice and _Aldh2__rs671_ mice

exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly

promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of

peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific

activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of

ALDH2 may be an effective treatment strategy for sepsis. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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INFLAMMATION AND IRON HOMEOSTASIS IN SEPSIS Article Open access 28 June 2024 ENAMPT NEUTRALIZATION REDUCES PRECLINICAL ARDS SEVERITY VIA RECTIFIED NFKB AND AKT/MTORC2 SIGNALING Article Open

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Scholar  Download references ACKNOWLEDGEMENTS This study was supported by the State Key Program of the National Natural Science Foundation of China (82030059), the National Science Fund for

Distinguished Young Scholars (82325031), the National Natural Science Regional Innovation Fund Joint Fund Key Support Projects (U23A20485), the National Natural Science Foundation of China

(82072144, 82172127), the National Key R&D Program of China (2020YFC1512700, 2020YFC1512705, 2020YFC1512703), the Key R&D Program of Shandong Province (2021ZLGX02, 2021SFGC0503,

2022ZLGX03), the Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), the Taishan Young Scholar Program of Shandong Province (tsqn202211312), the Clinical Research Project of

Shandong University (2021SDUCRCC006), and the Interdisciplinary Young Researcher Groups Program of Shandong University (2020QNQT004). Illustrations were made using BioRender. AUTHOR

INFORMATION Author notes * These authors contributed equally: Changchang Xu, Lin Zhang. AUTHORS AND AFFILIATIONS * Department of Emergency Medicine, Qilu Hospital of Shandong University,

Jinan, China Changchang Xu, Lin Zhang, Shaoyu Xu, Zichen Wang, Qi Han, Ying Lv, Xingfang Wang, Xiangxin Zhang, Qingju Zhang, Ying Zhang, Simeng He, Qiuhuan Yuan, Yuan Bian, Chuanbao Li, 

Jiali Wang, Feng Xu, Jiaojiao Pang & Yuguo Chen * Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and

Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China Changchang Xu, Lin Zhang, Shaoyu Xu, Zichen Wang, Qi Han, Ying Lv, Xingfang Wang, Xiangxin

Zhang, Qingju Zhang, Ying Zhang, Simeng He, Qiuhuan Yuan, Yuan Bian, Chuanbao Li, Jiali Wang, Feng Xu, Jiaojiao Pang & Yuguo Chen * 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, China Changchang Xu, Lin Zhang, Shaoyu Xu, Zichen Wang, Qi Han, Ying Lv, Xingfang Wang, Xiangxin Zhang, Qingju Zhang, Ying Zhang, 

Simeng He, Qiuhuan Yuan, Yuan Bian, Chuanbao Li, Jiali Wang, Feng Xu, Jiaojiao Pang & Yuguo Chen * The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry

of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu

Hospital of Shandong University, Jinan, China Changchang Xu, Lin Zhang, Shaoyu Xu, Zichen Wang, Qi Han, Ying Lv, Xingfang Wang, Xiangxin Zhang, Qingju Zhang, Ying Zhang, Simeng He, Qiuhuan

Yuan, Yuan Bian, Chuanbao Li, Jiali Wang, Feng Xu, Jiaojiao Pang & Yuguo Chen * Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, 171 65, Sweden Yihai

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Scholar CONTRIBUTIONS Y Chen and JP conceived and designed the experiments. CX and LZ performed most of the experiments with the help of SX, ZW, QH, YL, XW, XZ, QZ, YZ, SH, and QY CX, LZ,

SX, ZW, and YB performed the data analysis. Y Cao and JP assisted in revising the draft. CL, JW, and FX provided valuable experimental advice and guidance. All authors have read and approved

the final manuscript. CORRESPONDING AUTHORS Correspondence to Jiaojiao Pang or Yuguo Chen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare that the research was conducted in the

absence of any commercial or financial relationships that could be construed as potential conflicts of interest. SUPPLEMENTARY INFORMATION 41423_2024_1146_MOESM1_ESM.DOCX Sup Fig1-11,

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CITE THIS ARTICLE Xu, C., Zhang, L., Xu, S. _et al._ Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS. _Cell Mol Immunol_ 21, 510–526 (2024).

https://doi.org/10.1038/s41423-024-01146-w Download citation * Received: 03 October 2023 * Accepted: 09 February 2024 * Published: 12 March 2024 * Issue Date: May 2024 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * NETosis * ALDH2 * ARDS * Sepsis