To screen for biomarkers of chronic obstructive pulmonary disease (COPD) and myocardial infarction (MI) and explore potential common therapeutic targets.

Common differentially expressed genes (DEGs) of COPD and MI were identified based on GEO datasets and R language. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the DEGs. A protein-protein interaction (PPI) network was constructed using the STRING database, and key genes were screened in combination with weighted correlation network analysis (WGCNA). Expression of key genes was validated using external datasets. Immune infiltration analysis of MI datasets was conducted using the CIBERSORT algorithm to assess the correlation between key genes and immune cell infiltration levels. A transcription factor (TF)-miRNA coregulatory network was constructed. Candidate drug molecules with potential therapeutic effects on COPD-MI comorbidity were predicted.

Differential expression analysis of COPD and MI datasets based on the GEO database identified 49 DEGs. GO analysis showed that upregulated genes were mainly enriched in positive regulation of cytokines and pattern recognition receptor activity, while downregulated genes were enriched in leukocytemediated cytotoxicity. KEGG analysis revealed that upregulated genes were significantly enriched in the NF-κB signaling pathway, whereas no significant enrichment pathway was found for downregulated genes. Through PPI network and WGCNA analyses, six DEGs were selected. After validation with external datasets, three DEGs (TLR8, IL1B, and S100A12) were ultimately identified. Receiver operating characteristic (ROC) curves indicated that TLR8 and IL1B were associated with cigarette smoke exposure and recurrence of COPD complicated with MI. CIBERSORT analysis showed significant differences in the infiltration of 13 immune cell types between MI samples and controls. Singlesample Gene Set Enrichment Analysis (ssGSEA) revealed that key genes were negatively correlated with resting memory CD4⁺ T cells and positively correlated with monocytes, activated mast cells, and neutrophils. The TFmiRNA network suggested that the E2F1miR9TLR8 axis may be a common pathogenic pathway for the two diseases. Drug molecule prediction for the three key DEGs indicated that miglitol, TPEN and cycloheximide may have potential as common therapeutic agents for both diseases.

TLR8, IL1B and S100A12 may be therapeutic targets for COPD and MI. TLR8, IL1B serve as potential biomarkers and therapeutic targets for COPD-MI comorbidity. Cigarette smoke exposure may increase MI recurrence risk by affecting the TLR8/IL1B pathway. Neutrophil-mediated immune responses represent a crucial pathological feature shared by both diseases. Candidate drugs provide new research directions for comorbidity treatment. Miglitol, TPEN and cycloheximide may have potential therapeutic effects on both diseases.