【Abstract】 Objective To explore the regulatory role of methylation modification in chronic obstructive pulmonary disease (COPD), differentially methylated genes (DMGs) were screened with functional analyses in cigarette smoke (CS)-induced airway inflammation in mice. Methods Twenty male C57BL/6 mice were randomly divided into the control and cigarette smoke (CS) groups, which were respectively exposed to filtered air and CS for consecutive 4 weeks (2 hours twice daily, 6 days per week). After 4 weeks exposure, the lung tissues of mice were collected for HE staining and liquid hybridization capture-based bisulfite sequencing (LHC-BS). Differentially methylated regions (DMRs) and related differentially methylated genes (DMGs) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on DMGs. Results HE staining indicated four-week CS exposure significantly induced airway inflammation in mice. In total, 2569 DMRs were detected, of which 1309 DMRs were hypomethylated while 1260 DMRs were hypermethylated. 2002 DMGs, with 565 DMGs located in promoters, were further screened according to the corresponding gene annotations. The GO analysis suggested the DMGs were mainly enriched in cell differentiation, cell development, metabolic process, etc, and the KEGG analyses revealed that the DMGs were mainly enriched in Wnt, Hippo and Rap1 signaling pathways. Conclusion Methylation modification plays a major role in the CS-induced airway inflammation in mice, and the possible mechanism is that DMGs are implicated in mediating multiple inflammatory biological processes and signaling pathways.