Dexmedetomidine alleviates sepsis-induced acute lung injury by inhibiting M1 macrophage polarization via inhibition of PKM2-mediated Warburg effect

Yuyao He; Wanli Xie; Haifeng Zhou; Yanting Wang; Lu Chen; Zhenzhen Xu; Yiqi Feng; Guoyang Liu; Jie Liu; Xia Li; Yong Lv; Yunxiao Bai; Desheng Hu; Qingping Wu

doi:10.1016/j.bcp.2025.117130

Dexmedetomidine alleviates sepsis-induced acute lung injury by inhibiting M1 macrophage polarization via inhibition of PKM2-mediated Warburg effect

Biochem Pharmacol. 2025 Jul 5:117130. doi: 10.1016/j.bcp.2025.117130. Online ahead of print.

Authors

Yuyao He¹, Wanli Xie², Haifeng Zhou³, Yanting Wang², Lu Chen², Zhenzhen Xu², Yiqi Feng², Guoyang Liu², Jie Liu², Xia Li², Yong Lv², Yunxiao Bai², Desheng Hu⁴, Qingping Wu⁵

Affiliations

¹ Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China; Department of Anesthesiology, Nanchang First Hospital, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, China.
² Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China.
³ Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China.
⁴ Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 China. Electronic address: desheng.hu@hust.edu.cn.
⁵ Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China. Electronic address: 2003xh0883@hust.edu.cn.

PMID: 40623459
DOI: 10.1016/j.bcp.2025.117130

Abstract

Sepsis is a leading cause of in-hospital mortality, with more than 50% of patients developing Acute Lung Injury (ALI). Alveolar macrophages are the primary immune cells in lung tissue and play a crucial role in the pathogenesis of ALI. In this study, we investigated the potential therapeutic effects of dexmedetomidine (DEX) in both sepsis mice models of ALI and Lipopolysaccharide & Interferon gamma (LPS&IFN-γ)- stimulated macrophages, elucidating its underlying mechanism. In vivo experiments were conducted using the cecal ligation and puncture (CLP) technique to induce sepsis in mice, and intraperitoneal administration of DEX was initiated at 3, 6, 12 h post-CLP. Results showed that DEX significantly ameliorated CLP-induced lung tissue injury, impeded proinflammatory cytokine release, and reduced neutrophil infiltration. Additionally, DEX decreased M1 macrophage polarization in the lung tissue of septic mice. In vitro, experiments showed that DEX effectively attenuated the elevation of macrophage glycolysis levels induced by LPS & IFN-γ. Mechanistically, DEX treatment suppressed the phosphorylation of Pyruvate kinase M2 (PKM2) at the Y105 site and its nuclear translocation levels, thus disrupting the Warburg effect to reduce M1 cell polarization. Therefore, this work has demonstrated the role of DEX in macrophage polarization and sepsis-induced acute lung injury, providing valuable guidance for the treatment of critically ill patients with clinical sepsis.

Keywords: ALI; Dexmedetomidine; Macrophage; PKM2; Sepsis.