2. Academic Validation
  3. METTL3 promotes neutrophil extracellular trap formation via SYK/ERK/MEK signaling during acute lung injury

METTL3 promotes neutrophil extracellular trap formation via SYK/ERK/MEK signaling during acute lung injury

  • J Adv Res. 2026 Jan 22:S2090-1232(26)00069-X. doi: 10.1016/j.jare.2026.01.044.
Shuhua Luo 1,  Qianqian Zhang 1,  Wending Zhou 1,  Lina Zhang 1,  Chaoxiong Liao 1,  Dan Zeng 1,  Liangqing Zhang 2,  Fu-Li Xiang 3,  Jie Xu 4,  Jing Tang 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Guang Dong Medical University, Zhanjiang, Guangdong, China.
  • 2 Department of Anesthesiology, the Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
  • 3 Institute of Precision Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Sun Yat-sen University, Guangzhou, China; NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 4 Institute of Precision Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Sun Yat-sen University, Guangzhou, China; NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China. Electronic address: [email protected].
  • 5 Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Guang Dong Medical University, Zhanjiang, Guangdong, China. Electronic address: [email protected].
PMID: 41579954 DOI: 10.1016/j.jare.2026.01.044
Abstract

Introduction: Acute lung injury (ALI) is a life-threatening condition characterized by overwhelming pulmonary inflammation and neutrophil infiltration. Neutrophils play a central role in ALI pathogenesis by releasing proteolytic Enzymes, Reactive Oxygen Species, and neutrophil extracellular traps (NETs). Although NETs contribute to pathogen clearance, excessive NET formation exacerbates tissue injury and amplifies inflammation. N6-methyladenosine (m6A) is the most abundant internal modification of eukaryotic mRNA and plays a pivotal role in immune cell regulation by modulating RNA stability and translation. However, how m6A modification governs NETosis during ALI remains incompletely understood.

Objectives: This study aimed to investigate the role of METTL3 mediated m6A modification on NET formation and the underlying mechanisms in lung injury in ALI.

Methods: The role of METTL3 mediated m6A in ALI was examined in mouse with conditional deletion of METTL3 in myeloid or neutrophil lineages. Histological and flow cytometric analysis, gene interference, overexpression, transcriptomic profiling and m6A-RIP-qPCR were performed to elucidate the underlying mechanisms of METTL3 promoting NETosis via Syk/ERK/MEK signaling axis in vitro and in vivo.

Results: Conditional deletion of METTL3 in myeloid or neutrophil lineages significantly reduced lung MPO activity, citrullinated histone H3 levels, and extracellular DNA deposition following lipopolysaccharide (LPS)-induced ALI. METTL3 deficiency attenuated pulmonary inflammation and reduced neutrophil infiltration. In vitro, METTL3-deficient neutrophils exhibited decreased NET formation upon phorbol myristate acetate (PMA) stimulation, along with diminished Syk phosphorylation and downstream ERK/MEK activation. Mechanistically, METTL3 promotes m6A methylation of SYK mRNA, enhancing its stability and transcription. Pharmacological inhibition of either METTL3 or Syk recapitulated the protective phenotype, suppressing NETosis and lung damage in vivo.

Conclusion: Collectively, our findings uncover a novel METTL3-SYK epitranscriptomic axis that governs neutrophil effector responses during endotoxin-induced lung injury. These results highlight m6A-dependent post-transcriptional regulation as a potential therapeutic target in ALI and sepsis-associated inflammation.

Keywords

ALI; METTL3; Neutrophil extracellular trap; SYK; m6A.

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