Targeting myofibroblast copper vulnerability reverses pulmonary fibrosis via METTL3-directed STAT6 m6A driving cuproptosis

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) remains a fatal disease due to apoptosis-resistant myofibroblasts driving pathological extracellular matrix deposition. Current therapies fail to directly eliminate these cells, and cuproptosis-a copper-dependent cell death pathway-remains unexplored in pulmonary fibrosis. OBJECTIVES: We aimed to investigate whether copper ionophores induce selective myofibroblast death via cuproptosis and evaluate their antifibrotic effects. The study further explored the underlying molecular mechanisms involving STAT6 m6A methylation. METHODS: Copper ionophores were administrated to bleomycin-induced fibrotic mice to evaluate their antifibrotic effects and induction of cuproptosis. Primary fibroblasts isolated from mouse lungs were further employed for in vitro analysis. STAT6 fibroblast-conditional knockout (cKO) mice, as well as gain- and loss-of-function studies targeting METTL3 and IGF2BP2 were employed to explore potential mechanism. RESULTS: accumulation due to disruption of the STAT6-Nrf2-FDX1 axis. CONCLUSION: Copper ionophores induce cuproptosis to selectively eliminate myofibroblasts, reversing pulmonary fibrosis. The METTL3-STAT6-Nrf2 axis is identified as a druggable checkpoint, positioning copper ionophores as novel therapeutics for IPF.