Computational biology and chemistry · 2026
COPD-associated oxidative phosphorylation and electron transfer chain rewiring in circulating neutrophils and its relation to exacerbation and cognitive impairment.
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Beglari Farzin, Ghobadi Hassan, Shabani-Mashcool Soheila, Kavousi Kaveh, Khodarahmi Reza, Mehrabi Masomeh, Azim M Kamran, Amani Mojtaba
Аннотация
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder linked to increased oxidative stress. Oxidative phosphorylation (OXPHOS) and electron transport chain (ETC) activity in circulating neutrophils generate reactive oxygen species (ROS), potentially associated with disease exacerbation and cognitive impairment. This study aimed to identify OXPHOS-related hub genes in neutrophils, investigate COPD-associated network rewiring, and assess their associations with disease progression and neurodegeneration.
MATERIALS AND METHODS: Gene expression data from GSE278206 were analyzed using weighted gene co-expression network analysis (WGCNA) in R to identify co-expression modules. Functional enrichment (GO and KEGG) was performed with clusterProfiler. Correlation rewiring was assessed using Hmisc and Fisher's z-transformation test. Protein-protein interaction (PPI) networks were constructed via STRING database (v12) and Cytoscape (v3.10.3), with MCODE (v2.0.3) for module detection and ClueGO (v2.5.10) for functional annotation. Drug-gene interactions were explored using the drug-gene interaction database (DGIdb).
RESULTS: The turquoise module exhibited strong positive correlations with COPD in males (r = 0.93, adjusted p = 0.03) and females (r = 0.45, adjusted p = 2.48 × 10⁻⁶) and was enriched in OXPHOS/ETC genes. COPD-associated network rewiring showed strengthened correlations, particularly involving COX7A2P2, with potential inhibition by Metformin hydrochloride, ME-344, NV-128, and HET0016. OXPHOS genes displayed strong rewiring inflammatory response genes (notably IL6ST) and neutrophil activation genes (notably PREX1) in COPD versus controls.
CONCLUSION: OXPHOS- and ETC-related hub genes in circulating neutrophils are associated with COPD-associated transcriptional rewiring, with COX7A2P2 emerging as a strong candidate, potentially contributing to incident COPD and therapeutic targets.
MATERIALS AND METHODS: Gene expression data from GSE278206 were analyzed using weighted gene co-expression network analysis (WGCNA) in R to identify co-expression modules. Functional enrichment (GO and KEGG) was performed with clusterProfiler. Correlation rewiring was assessed using Hmisc and Fisher's z-transformation test. Protein-protein interaction (PPI) networks were constructed via STRING database (v12) and Cytoscape (v3.10.3), with MCODE (v2.0.3) for module detection and ClueGO (v2.5.10) for functional annotation. Drug-gene interactions were explored using the drug-gene interaction database (DGIdb).
RESULTS: The turquoise module exhibited strong positive correlations with COPD in males (r = 0.93, adjusted p = 0.03) and females (r = 0.45, adjusted p = 2.48 × 10⁻⁶) and was enriched in OXPHOS/ETC genes. COPD-associated network rewiring showed strengthened correlations, particularly involving COX7A2P2, with potential inhibition by Metformin hydrochloride, ME-344, NV-128, and HET0016. OXPHOS genes displayed strong rewiring inflammatory response genes (notably IL6ST) and neutrophil activation genes (notably PREX1) in COPD versus controls.
CONCLUSION: OXPHOS- and ETC-related hub genes in circulating neutrophils are associated with COPD-associated transcriptional rewiring, with COX7A2P2 emerging as a strong candidate, potentially contributing to incident COPD and therapeutic targets.