A comprehensive cuproptosis score and associated gene signatures reveal prognostic and immunological features of idiopathic pulmonary fibrosis

BACKGROUND: Cuproptosis, the most recently identified and regulated cell death, depends on copper ions in vivo. Copper regulates the pathogenesis of Idiopathic pulmonary fibrosis (IPF), but the mechanism of action underlying cuproptosis in IPF remains unclear. METHODS: We identified three cuproptosis patterns based on ten cuproptosis-related genes using unsupervised consensus clustering. We quantified these patterns using a PCA algorithm to construct a cuproptosis score. ssGSEA and the Cibersort algorithm assessed the immune profile of IPF patients. GSEA and GSVA were used to analyze the functional differences in different molecular patterns. Drug susceptibility prediction based on cuproptosis scores and meaningful gene markers was eventually screened in combination with external public data sets,in vitro experiments and our cases. RESULTS: Of the three types of cuproptosis-related clusters identified in the study, patients in the clusterA, geneclusterB, and score-high groups showed improved prognoses. Moreover, each cluster exhibited differential immune characteristics, with the subtype showing a poorer prognosis associated with an immune overreaction. Cuproptosis score can be an independent risk factor for predicting the prognosis of IPF patients. GSEA showed a significant functional correlation between the score and cuproptosis. The genes AKAP9, ANK3, C6orf106, LYRM7, and MBNL1, were identified as prognostic-related signatures in IPF patients. The functional role of immune regulation in IPF was further explored by correlating essential genes with immune factors. Also, the nomogram constructed by cumulative information from gene markers and cuproptosis score showed reliable clinical application. CONCLUSIONS: Cuproptosis patterns differ significantly in the prognosis and immune characteristics of IPF patients. The cuproptosis score and five gene signatures can provide a reliable reference in the prognosis and diagnosis of IPF.