Candida-associated immune and metabolic rewiring in chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent systemic inflammation. Candida colonization is frequently observed in patients with COPD, yet its systemic impact remains poorly understood. This study aimed to identify molecular alterations uniquely induced by Candida under COPD conditions. METHODS: An interaction-based model incorporating COPD status, Candida colonization, and their interaction term was used to define COPD-context-dependent Candida-responsive genes and metabolites. Peripheral blood mononuclear cell transcriptomes were analyzed by RNA sequencing, followed by functional enrichment, protein-protein interaction (PPI), and transcription factor (TF) motif analyses. Plasma metabolomics was performed to identify exclusive differential metabolites and enriched pathways. Multi-omic integration was performed to assess coordinated relationships between genes and metabolites, with correlation network construction and Spearman's correlation validation. RESULTS: A subset of differentially expressed genes (DEGs) was exclusively altered in the CA_COPD versus COPD comparison. These genes were primarily enriched in immune regulation and inflammatory signaling pathways. PPI analysis identified limited but biologically meaningful interaction networks, while TF motif analysis implicated the zf-C2H2 family as a potential regulator of context-specific transcriptional remodeling. Metabolomic profiling revealed exclusive differential metabolites in CA_COPD. Upregulated metabolites were marginally associated with amino sugar and nucleotide sugar metabolism, whereas downregulated metabolites were significantly enriched in aminoacyl-tRNA biosynthesis, central carbon metabolism, protein digestion and absorption, and ABC transporter pathways. Integrated multi-omic analysis demonstrated tightly coordinated gene-metabolite networks linking transcriptional and metabolic reprogramming under Candida-COPD interaction conditions. CONCLUSION: Candida colonization induces distinct COPD-context-dependent transcriptional and metabolic reprogramming, suggesting a specific host response signature that may contribute to disease progression.