Integrated multi-omics analysis supports a causal association of chronic obstructive pulmonary disease with benign prostatic hyperplasia and interactions between VCAN-high fibroblasts and macrophages in hyperplastic prostate tissue

Background Chronic obstructive pulmonary disease (COPD) and benign prostatic hyperplasia (BPH) are common among middle-aged and older men and can coexist clinically. However, the direction of causality and the underlying biological links between them remain unclear. Methods The population-level association between COPD and BPH was evaluated using data from the National Health and Nutrition Examination Survey (NHANES), and Mendelian randomization (MR) was used to assess potential causal directions and immune-related genetic features. We integrated transcriptomic analyses of both diseases and used differential expression, functional enrichment, co-expression network analysis, and machine learning to characterize disease-associated transcriptional profiles and identify shared candidate genes. Single-cell and spatial transcriptomic analyses were further used to determine the cellular localization of the key candidate, characterize associated functional states, and assess potential cell-cell interactions. Finally, core mechanisms were validated through co-culture, immunofluorescence, and other experiments. Results NHANES analysis showed that COPD was significantly associated with prevalent BPH. MR supported a causal effect of COPD on BPH risk; this finding remained stable in multivariable analyses, whereas reverse MR showed no clear effect. Immunogenetic analyses suggested partially overlapping immune features in the two diseases, and transcriptomic findings further converged on immune-inflammatory and extracellular matrix (ECM) remodeling-related changes. VCAN was identified as a shared key candidate gene that was consistently upregulated in both diseases and validated in external cohorts. Single-cell analysis showed that VCAN was expressed predominantly in prostatic fibroblasts; high VCAN expression was associated with higher inflammatory response and ECM remodeling scores and with predicted communication and spatial associations with macrophages. In vitro , co-culture with M1-like macrophages enhanced VCAN expression, proliferation, and ECM remodeling-related phenotypes in WPMY-1 cells, whereas VCAN silencing attenuated these changes. Conclusions This study provides evidence that COPD increases BPH risk and suggests that the two diseases have partially shared immune-inflammatory and ECM remodeling features. VCAN may contribute to prostatic stromal cell proliferation and ECM remodeling induced by macrophage-associated inflammation.