Abstract: Objective: To investigate the expression of lipid metabolism-related genes in chronic obstructive pul-monary disease (COPD) and explore the possible mechanism of key lipid metabolism-related genes in COPD.Methods: Data were obtained from GEO and GeneCards databases, and the differentially expressed lipid metabo-lism genes were screened out by GO enrichment and PPI network analysis.A mouse model of emphysema was es-tablished after 24 weeks of cigarette exposure, and the lung histopathological changes were observed by HE stain-ing.Real-time fluorescence quantitative polymerase chain reaction(RT-qPCR)was used to detect the mRNA rela-tive expression levels of key genes in lipid metabolism in mouse lung tissue.Normal human lung epithelial cell line BEAS-2B was interfered with cigarette smoke extract.The intervention concentration of cigarette smoke ex-tract was determined by cell counting kit (CCK-8), and the relative expression levels of key lipid metabolism genes in BEAS-2B cells were determined by RT-qPCR.Results: Five key genes of lipid metabolism (PIK3CA, PRKAG2, GNB3, PLCB2, GLA) were screened based on GEO and GeneCards databases. PIK3CA and PRKAG2 genes were found to be highly expressed in small airway epithelial cells in smoking-related COPD, while GNB3, PLCB2 and GLA genes were down-regulated.Compared with the wild-type control group, the successfully con-structed emphysema mouse model showed that PIK3CA and PRKAG2 mRNA expressions increased (P< 0.001), while GNB3, PLCB2 and GLA mRNA expressions were down-regulated (P< 0.001), which was consis-tent with the gene expression in BEAS-2B cells inter-fered with cigarette smoke extract.Conclusion: Key lipid metabolism genes PIK3CA, PRKAG2, GNB3, PLCB2 and GLA are involved in the occurrence and development of COPD, and may be potential biomarkers for the identification of smoking-related COPD.