Acute lung injury (ALI) is a critical clinical condition characterized by diffuse inflammation of the lung parenchyma and intractable hypoxemia, typically caused by factors, such as trauma, pneumonia, shock, and sepsis. Clinical symptoms of ALI include pulmonary edema, impaired gas exchange, and hypoxemia.
m6A methylation regulates gene expression by influencing RNA translation, splicing, stability, and export. This process is dynamically controlled by m6A writers, such as methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14), which install the m6A mark; m6A erasers such as fat mass and obesity-associated (FTO) and AlkB homolog 5, RNA demethylase (ALKBH5) proteins that remove the m6A mark; and m6A readers such as YTH domain-containing family protein 1 (YTHDF1) and insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) that recognize the m6A mark and execute functions like RNA degradation or translation.
In a comprehensive review, published online in the Journal of Intensive Medicine on August 20, 2025, the authors elucidate the molecular mechanisms of m6A methylation and its associated proteins in ALI pathogenesis. “ This review synthesizes and summarizes findings from multiple groundbreaking studies,” stated Professor Fangwei Li, Lanzhou University Second Hospital, China, who is the corresponding author for this study.
Besides, the review notes that some studies report contradictory results. It analyzes several potential causes:
1. The dynamic nature of m6A methylation means data collected at different time points post-modeling may yield conflicting conclusions.
2. Levels of m6A-related proteins vary significantly between different lung cell types, and studying different cells can lead to different outcomes.
3. Current studies use diverse methods to establish ALI models (e.g., intraperitoneal LPS injection, intratracheal instillation, CLP surgery). LPS concentration can critically impact cellular responses.
Future directions:
Translation to clinical validation: Current research findings are predominantly based on animal studies. Future efforts need to translate these discoveries into clinical settings and validate them using human clinical data.
“Elucidating cell-type-specific regulation: Research should investigate intercellular interactions and elucidate the precise regulatory mechanisms of m6A in different pulmonary cell types,” said Dr. Yating Hu, another author associated with the study. Concurrently, it is crucial to conduct larger-scale clinical studies with expanded patient cohorts.
In the future, integrating multiomics analysis with nanodelivery technologies will be crucial for advancing precision therapies.
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Reference
DOI: 10.1016/j.jointm.2025.07.001
Journal of Intensive Medicine
Literature review
Not applicable
N6-methyladenosine methylation in acute lung injury: Mechanisms and research progress
20-Aug-2025
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.