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; p = 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.