The NDUFS1/BRK1 Axis in COPD Pathogenesis: A Multi-Omics Approach Linking Mitochondrial Dysfunction to Actin Cytoskeleton Disruption

Background: Chronic obstructive pulmonary disease (COPD) is a major global health burden, affecting over 300 million people and ranking as the third leading cause of death worldwide. Current therapies do not modify disease progression, and molecular mechanisms linking mitochondrial dysfunction and cytoskeletal disruption remain unclear. Emerging evidence implicates NDUFS1, a subunit of mitochondrial complex I, and BRK1, a key regulator of actin cytoskeleton dynamics, in COPD pathogenesis, potentially through related pathways. Methods: We conducted an integrative multi-omics study combining transcriptomic profiling of lung tissues from COPD patients and healthy controls, two-sample Mendelian randomization(MR) using genome-wide association study summary statistics, and network pharmacology coupled with molecular docking. Transcriptomic analyses assessed differential expression of NDUFS1 and BRK1, their correlation with clinical parameters such as forced vital capacity and GOLD stages, and pathway-level changes via gene set enrichment analysis. MR used inverse variance weighted method as primary analysis, supported by MR-Egger, weighted median, and mode-based approaches, with sensitivity tests for pleiotropy. Network pharmacology identified compounds targeting NDUFS1, followed by docking to evaluate binding affinities. Results: Transcriptomic results showed NDUFS1 upregulation and BRK1 downregulation in COPD. BRK1 decreased across GOLD stages and correlated positively with forced vital capacity. Gene set enrichment analysis revealed suppression of the actin cytoskeleton pathway, strongly negatively correlated with NDUFS1 and positively with BRK1. MR indicated a protective causal effect of BRK1 on COPD risk, with consistent directional support across methods. Higher NDUFS1 expression causally reduced BRK1 levels, with no significant pleiotropy. β-sitosterol showed the strongest predicted binding affinity to NDUFS1 among screened phytochemicals. Conclusion: Dysregulation of NDUFS1 and BRK1 may contribute to COPD via mitochondrial-cytoskeletal crosstalk. Causal evidence supports further investigation, with β-sitosterol emerging as a candidate for therapeutic development.