Abstract:Objective To preliminarily predict and verify the biological mechanism and potential core therapeutic targets of chronic obstructive pulmonary disease (COPD)-associated lung cancer （COPD-LC） based on proteomics analysis combined with bioinformatics technology. Methods Urine samples of COPD, lung cancer patients and healthy people who visited the outpatient clinic of the Fourth Clinical Medical College of Xinjiang Medical University from December 2018 to August 2021 were collected and sequenced by high-throughput sequencing. Differential proteins were screened, protein-protein interaction (PPI) network diagrams were constructed, functional enrichment analysis was carried out to further predict the key targets of COPD-LC, and finally the above molecules were verified in the Gene Expression Omnibus (GEO) database. Results Proteomics results showed that there were 157 differential proteins in the COPD group compared with the normal control group, including 67 up-regulated proteins and 90 down-regulated proteins. Compared with the normal control group, there were 306 differential proteins in the lung cancer group, including 132 up-regulated and 174 down-regulated proteins. In addition, PPI analysis was performed for the above differential proteins based on the Search Tool for the Retrieval of Interacting Genes (STRING) platform. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes （KEGG） analysis showed that COPD-LC was mainly enriched in extracellular region, lysosomes, extracellular space, amylase activity, protease inhibitor activity, defense/immune protein activity and other aspects. The microarray data of COPD and lung cancer were searched in the GEO database, and GSE8581 and GSE43346 were finally included. A total of 13 605 differential genes were identified in GSE8581 dataset, and 3 403 differential genes were identified in GSE43346 dataset. The degree of overlap between the differential genes in the GSE8581 and GSE43346 datasets was further analyzed, and 4 overlapping proteins were found in the two, including latent TGF-β binding protein (LTBP) 4, N-acetyl-alpha-glucosaminidase (NAGLU), ubiquitin protein ligase E3 component N-recognin (UBR) 4, and DNA damage binding protein 1 and cullin-ring ligase 4 associated factor (DCAF) 5, which were verified in the GEO database finally. Conclusion This study has initially revealed 4 potential therapeutic targets for COPD-LC, including LTBP4, NAGLU, UBR4 and DCAF5, among which NAGLU, UBR4 and DCAF5 are rarely reported in the research of COPD and lung cancer. The above proteins are significantly low expressed in COPD and lung cancer, and may become significant biomarkers for the diagnosis and treatment of COPD-LC.