Berbamine Targets TNFAIP3: A Bioactive Compound Alleviates Oxidative Stress and Inflammation in the Comorbidity of Insomnia and Chronic Obstructive Pulmonary Disease Through Multi-Omics Integration

Chronic obstructive pulmonary disease (COPD) and insomnia are highly comorbid, yet their shared pathogenesis and therapeutic targets remain unclear. This study employed multidimensional approaches-including bidirectional Mendelian randomization (MR), transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and computational drug repositioning-to investigate causal relationships, shared pathways, and therapeutic strategies for COPD-insomnia comorbidity. MR analysis indicated that insomnia is a causal risk factor for COPD (OR = 2.04, 95% CI: 1.18-3.51; <i>p</i> = 0.011), with no reverse causality. Integrated transcriptomics of COPD (GSE148004) and insomnia (GSE208668) identified 230 co-dysregulated genes enriched in immune-inflammatory pathways (e.g., NF-κB signaling and cytokine response) and oxidative stress. Protein-protein interaction networks highlighted TNFAIP3 as a hub gene, confirmed by LASSO regression as a shared diagnostic biomarker. A co-expression network of 190 overlapping genes linked circadian disruption and airway inflammation. Drug repositioning nominated TNFAIP3-targeting agents, and molecular docking revealed high-affinity binding between berbamine and the TNFAIP3 OTU domain (ΔG = -9.25 kcal/mol). TNFAIP3 emerges as a dual regulator of inflammatory signaling and redox homeostasis. Our systems pharmacology approach bridges epidemiological causality and molecular mechanisms, supporting single-agent polypharmacology for COPD-insomnia comorbidity.