Targeting cuproptosis: a potential new therapeutic strategy for idiopathic pulmonary fibrosis

Background Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease, and currently, there are no effective means to reverse its progression. Cuproptosis is a newly discovered copper-dependent programmed cell death mechanism, but its role in IPF remains unknown. This study aimed to investigate whether Cuproptosis is involved in the pathogenesis of IPF and to evaluate its potential as a therapeutic target.Methods In vitro, a fibrosis model was induced in human lung epithelial cells by bleomycin treatment. In vivo, a C57BL/6J mouse IPF model was established by intratracheal instillation of bleomycin. The effects on fibrosis progression were observed using the Cuproptosis inhibitor ammonium tetrathiomolybdate and siRNA knockdown of the copper ion transporter Slc31a1.Results Significant Cuproptosis was observed in both BLM-induced lung epithelial cells and mouse lung tissue. Gene expression profiling identified key Cuproptosis-related genes, including Slc31a1. Pharmacological inhibition of Cuproptosis effectively reversed the Cuproptosis process in both in vitro and in vivo models and significantly reduced fibrotic pathological changes. At the cellular level, knockdown of Slc31a1 mimics the protective effect of TTM; however, its efficacy in whole animal models is limited.Conclusion This study identifies cuproptosis as a significant contributor to the pathogenesis of pulmonary fibrosis. Pharmacological inhibition of this pathway alleviates disease phenotypes, supporting the feasibility of targeting copper metabolism.