Abstract
BACKGROUND: An increasing number of studies have demonstrated a strong correlation between metabolism, inflammation, and chronic obstructive pulmonary disease (COPD). However, it remains unclear if there is a causal relationship between these factors. This study employed the Mendelian randomization (MR) approach to investigate the associations between these factors and explore the mediating roles of key inflammatory proteins. METHODS: MR was used to assess the causal associations between plasma metabolites, inflammatory proteins, and COPD. Sensitivity analyses were performed to verify the robustness of the findings. Mediation analysis was conducted to explore the roles of inflammatory proteins in the metabolism-COPD pathway. We constructed protein-protein interaction (PPI) network and explored the potential mechanism through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Single-cell sequencing and transcriptome datasets were used for auxiliary validation. Finally, experimental validation was performed using human lung tissue. RESULTS: This study identified 63 metabolites, 10 metabolite ratios, and 48 inflammatory proteins that were associated with COPD, all of which exhibited potential causal relationships. Furthermore, three proteins were identified as mediators in the metabolite-to-COPD pathway. PPI network, GO and KEGG enrichment analysis revealed the biological pathways in which they were involved. Validation of the expression of these three intermediary proteins in lung tissue demonstrated that NRXN3 was expressed in pulmonary endothelial cells and exerted a protective effect against COPD development. CONCLUSION: The MR analysis revealed causal associations among metabolism, inflammation, and COPD. These findings offer novel insights into metabolism-inflammation-COPD mechanisms, suggesting that interventions targeting metabolic processes may represent a promising strategy for preventing the onset or progression of COPD.