Identification of GSR and CBR1 as biomarkers in HIV ‐associated emphysema through transcriptomic analysis

Background With the widespread use of antiretroviral therapy (ART), life expectancy among people living with human immunodeficiency virus (HIV) infection has significantly increased. However, studies on HIV‐associated emphysema, especially those addressing the mechanisms, remain limited. In this study, we analysed transcriptomic data from Gene Expression Omnibus (GEO) to investigate the underlying mechanisms and identify biomarkers of HIV‐associated emphysema. Methods The gene expression profiling data of HIV infection (GSE76246, peripheral blood samples), emphysema (GSE11906, airway tissue samples) and HIV‐associated emphysema (GSE76403, peripheral blood samples) were obtained. We performed differential expression gene (DEG) analysis, functional enrichment analysis, weighted gene co‐expression network analysis (WGCNA), protein‐protein interaction (PPI) network analysis and random forest modelling to explore the mechanisms and candidate biomarkers of HIV‐associated emphysema. The expression of candidate biomarkers was subsequently validated in the comorbidity dataset, and immune cell infiltration was assessed. Results We identified genes shared between HIV infection and emphysema and trait‐relevant modules. Functional enrichment analysis suggested that persistent immune activation, altered RNA metabolism, protein translation, enhanced oxidative stress responses and potential adverse effects of ART via P450 might contribute to HIV‐associated emphysema. PPI network analysis and random forest modelling identified Glutathione‐disulphide reductase (GSR) and Carbonyl reductase 1 (CBR1) as candidate biomarkers, which were preliminarily supported by findings from the comorbidity dataset. Immune cell infiltration analyses indicated increased proportions of memory B cells, activated dendritic cells, CD8+ T cells, gamma delta T cells and Tregs, along with decreased levels of resting mast cells and naive CD4+ T cells in HIV‐associated emphysema. Conclusion Our study suggests possible mechanisms and candidate biomarkers (GSR and CBR1) for HIV‐associated emphysema and also provides exploratory insights into potential immune dysregulation in affected patients. However, due to the heterogeneity of tissue sources, limited sample size and the fact that the mechanistic insights were inferred from bioinformatics analyses rather than experimental validation, the cross‐tissue relevance of shared genes remains speculative and the immune infiltration findings based on peripheral blood transcriptomes may not fully reflect lung immune composition. Therefore, these findings should be interpreted with caution.