Contribution of cuproptosis and Cu metabolism‐associated genes to chronic obstructive pulmonary disease

Abstract

Airway epithelial cell injury plays a crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, a novel form of Cu‐induced programmed cell death known as cuproptosis has not yet been thoroughly investigated in the context of COPD. Clinical reports have suggested that high copper exposure may increase the risk of COPD. In this study, we aimed to determine the expression and potential functions of cuproptosis‐related genes and genes associated with copper metabolism in COPD. We initially identified 52 copper metabolism‐related genes based on a review of the literature. Subsequently, we calculated the expression levels of these genes using data from four GEO datasets. To gain insights into the activated signalling pathways and underlying mechanisms in COPD patients, we conducted Gene Ontology (GO) and KEGG pathway analyses, examined protein–protein interactions, and performed weighted correlation network analysis. Our findings revealed that 18 key copper metabolism‐related genes, including 5 cuproptosis‐related genes, were significantly enriched in signalling pathways and biological processes associated with the development of COPD. Further analysis of clinical data and animal experiments confirmed the high expression of certain cuproptosis key regulators, such as DLD and CDKN2A, in both healthy smokers and COPD smokers. Additionally, these regulators exhibited abnormal expression in a COPD rat model. Notably, copper content was found to be elevated in the lung tissues of COPD rats, suggesting its potential involvement in cuproptosis. These findings provide an experimental foundation for further research into the role of cuproptosis in COPD. Targeting copper metabolism‐related genes may represent an effective approach for the treatment of COPD.

Copper homeostasis dysregulation in respiratory diseases: a review of current knowledge

“…Qi et al found that 18 key Cu metabolization-related genes were significantly enriched in signaling pathways and biological processes associated with COPD development. DLD and CDKN2A are abnormally expressed in the airway epithelial cells of patients with COPD, and smoking can promote their expression to a certain extent, which has been verified in murine models of COPD (Qi et al, 2023). These findings suggest that the occurrence of COPD is related to the expression of Cu-regulatory genes.…”

“…The exhaled breath condensate (EBC) of patients with stable COPD had lower Cu levels than those of the controls, and Cu levels in the EBC were positively related to FEV1 in subjects with COPD (Mutti et al, 2006). Elevated Cu levels have also been found in the lungs of rats with COPD (Qi et al, 2023). Cu deficiency induces emphysema in animal models (Mizuno et al, 2012).…”

Unveiling the role of copper metabolism and STEAP2 in idiopathic pulmonary fibrosis molecular landscape

“…Our study focus on the differential expression of 52 genes associated with cuproptosis and Cu metabolism 22 between IPF and control groups (Figure 2A). In the IPF group (Figure 2B), a total of 14 DEGs were identified.…”

Association between Serum Copper, Copper/Selenium Ratio and Risk of Chronic Obstructive Pulmonary Disease in Smokers and Non-smokers: A cross-sectional study of NHANES 2011-2016

“…The study revealed a linear positive correlation between Cu levels and COPD mortality risk [34] . Qi W et al identi ed that apoptosis induced by Cu is a signi cant contributor to the development of COPD [20] . In the study, researchers established a COPD rat model and identi ed key regulators of copper-induced apoptosis (cuproptosis), primarily DLD and CDKN2A.…”

“…Research indicates that patients' serum Cu levels rise with increasing clinical severity of COPD exacerbations, suggesting they could serve as a marker for the condition's clinical deterioration [19] . A study revealed that 18 copper metabolism genes, including 5 linked to cuproptosis, play a signi cant role in COPD development through key signaling pathways and biological processes [20] . In humans, Se is integrated into selenoproteins in the form of selenocysteine.…”