Abstract

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 Our results show that copper ionophores significantly reduced lung collagen and eliminated α-SMA + myofibroblasts in mice. Mechanistically, these ionophores suppressed METTL3-mediated m6A methylation in fibroblasts, leading to destabilization of STAT6 mRNA and inhibition of its m6A signatures. This abrogated STAT6′s regulation on copper homeostasis, impairing copper efflux via ATP7A downregulation and causing toxic Cu + 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.