Understanding the role of m6A methylation in the pathogenesis of acute lung injury

Acute lung injury (ALI) is a critical clinical condition characterized by diffuse inflammation of the lung parenchyma and intractable hypoxemia, usually 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 affecting RNA translation, splicing, stability, and export. This process is dynamically controlled by m6A registrars, such as methyltransferase 3 (METTL3) and methyltransferase 14 (METTL14), which establish the m6A signal. 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 signal and perform functions such as RNA degradation or translation.

In a comprehensive review, published online at Journal of Intensive Medicine Aug 20, 2025 The authors elucidate the molecular mechanisms of methylation of m6A and its associated proteins in the pathogenesis of ALI. “This review synthesizes and summarizes findings from multiple pioneering studies.” said Professor Fangwei Li, Lanzhou University Second Hospital, China, who is the corresponding author for this study.

1. m6A Authors:

   • METTL3: METTL3 exacerbates lung injury by modifying key genes and non-coding RNAs. Downregulation of METTL3 reduces alveolar epithelial cell (AEC) apoptosis, inflammation, and pyroptosis.
   • METTL4: Deletion reduces ferrocytosis-related markers and ameliorates ferrocytosis in AECs.
   • METTL14: Knockdown significantly reduces baseline levels of inflammatory cytokines and directly inhibits inflammasome activation, thereby reducing lung tissue damage and swelling.

2. m6A erasers:

   • FTO: Knock-out alleviates alveolar structural disruption, tissue edema and pulmonary inflammation. In addition, increased FTO suppresses miRNA function, subsequently enhancing inflammatory pathways and damaging macrophage responses, exacerbating lung injury in obese mice.
   • ALKBH5: ALKBH5 promotes ferroptosis by stabilizing a circular RNA (circRNA).

3. m6A Readers:

   • YTHDF1: YTHDF1 affects mitochondrial function, M1 macrophage polarization, and proinflammatory functions, exacerbating the inflammatory response in ALI.
   • IGF2BP3: IGF2BP3 expression is increased in lung tissue from patients with acute respiratory distress syndrome.

In addition, the review notes that some studies report conflicting results. It analyzes several possible causes:
1. The dynamic nature of m6A methylation means that data collected at different time points after modeling may yield conflicting conclusions.
2. Levels of m6A-related proteins vary significantly between different lung cell types, and studying different cells may lead to different results.
3. Current studies use a variety of methods to generate ALI models (eg, intraperitoneal injection of LPS, intratracheal instillation, CLP surgery). LPS concentration can critically affect cellular responses.

Future directions:

Translation into clinical validation: Current research findings are based primarily on animal studies. Future efforts need to translate these discoveries into clinical settings and validate them using human clinical data.

“Clarifying regulation by cell type: Research should explore intercellular interactions and elucidate the precise regulatory mechanisms of m6A in different lung cell types.” said Dr. Yating Hu, another author associated with the study. At the same time, it is important to conduct larger-scale clinical studies with expanded groups of patients.

In the future, the integration of polyomic analysis with nanofabrication technologies will be crucial to advance precision therapies.