ArticleJournal of advanced research2026
METTL3 promotes neutrophil extracellular trap formation via SYK/ERK/MEK signaling during acute lung injury.
Article in Journal of advanced research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- PDHA1 Hyperactivation-Mediated Glucose Metabolism Reprogramming Fuels Neutrophil NETosis and Promotes Acute Lung Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Epigenetic regulation of neutrophil dysfunction in sepsis: mechanisms, biomarkers, and translational challenges.Journal of translational medicine · 2026Review
- The Role of NMedComm · 2026Review
- Review
- Polydatin Attenuates Sepsis-Induced Lung Injury by Inhibiting Neutrophil Extracellular Traps Formation via Nrf2/HO-1 Pathway.Biomedicines · 2026Article
- Neutrophil-macrophage crosstalk network in acute lung injury: feedback circuits linking cytokine storm and cell death.Frontiers in cellular and infection microbiology · 2026Review
- mFrontiers in immunology · 2026Review
- N6-methyladenosine as a potential epitranscriptomic immune rheostat during SARS-CoV-2 infection.Frontiers in immunology · 2026Review
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionAcute 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.
objectivesThis study aimed to investigate the role of METTL3 mediated m6A modification on NET formation and the underlying mechanisms in lung injury in ALI.
methodsThe 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.
resultsConditional 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.
conclusionCollectively, 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.
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