Proteo-metabolomic insights into the progression of chronic obstructive pulmonary disease and lung function decline

Chronic obstructive pulmonary disease (COPD) is a progressive yet preventable respiratory disease, often remaining undiagnosed until significant lung function impairment has occurred. The early, asymptomatic stage, termed "pre-COPD", offers a critical window for intervention, yet its molecular characteristics remain poorly understood.

We performed integrated proteomic and metabolomic profiling of human lung tissues across the spectrum of COPD (n = 32), including non-diseased controls, individuals with pre-COPD, and patients at varying stages of established disease. Key molecules and pathways involving in the progression of COPD were revealed. The performance of candidate biomarkers for monitoring early-stage lung function decline was validated in serum samples from an independent cohort (n = 158), and a longitudinal cohort from the UK Biobank (n = 21,686).

Pairwise comparisons revealed 751 proteins and 1,024 metabolites that were differentially abundant among groups. Pathways such as pyrimidine metabolism and arginine biosynthesis were revealed associated with disease progression. Notably, we identified a core protein-protein interaction network modulated by zinc and copper, two clinically used, orally available trace elements, highlighting their potential as candidate therapeutic agents for COPD. Furthermore, integrative analysis with an independent blood-based cohort and longitudinal data from the UK Biobank uncovered choline as a circulating biomarker that predicts longitudinal lung function decline.

Our findings define a molecular atlas of pre-COPD, identify actionable therapeutic targets, and propose a readily measurable biomarker for early detection and risk stratification of COPD.