m⁶A modification regulates lung fibroblast-to-myofibroblast transition through modulating KCNH6 mRNA translation

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N⁶-methyladenosine (m⁶A) modification has been implicated in various biological processes. However, the role of m⁶A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m⁶A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m⁶A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m⁶A-regulated FMT process. m⁶A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m⁶A modification in pulmonary fibrosis. Manipulation of m⁶A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis.