m6A methylation regulatory network in pulmonary fibrosis: Molecular mechanisms from RNA stability to cellular phenotype transition (Review).

Pulmonary fibrosis (PF) is a progressive and often irreversible interstitial lung disease characterized by aberrant wound healing, excessive extracellular matrix deposition and distortion of lung architecture. N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, dynamically regulates RNA metabolism through m6A writers, erasers and readers. Evidence indicates that m6A dysregulation contributes to PF by modulating fibroblast activation, epithelial injury and senescence, epithelial-mesenchymal plasticity, macrophage-associated inflammation, oxidative stress responses and extracellular matrix remodeling. In the present review, the expression characteristics and functional alterations of m6A machinery in fibrotic lung tissue, the role of m6A-mediated epitranscriptomic remodeling in pulmonary cell fate determination and the potential translational value of m6A regulators as biomarkers and therapeutic targets are summarized. In addition, particular focus is placed on cell-type-specific and context-dependent mechanisms, including the distinct roles of METTL3, METTL14, FTO, ALKBH5 and YTHDF proteins in different fibrotic settings. The present review highlights that m6A modification is not a uniform pro-fibrotic or anti-fibrotic switch, but rather a dynamic regulatory network that links RNA metabolism to PF progression and therapeutic opportunities.