Divergent plasma lipidomic signatures characterizing the pathophysiological heterogeneity of COPD and pulmonary fibrosis.
BACKGROUND Chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis (PF) represent divergent respiratory pathologies, yet their systemic metabolic drivers remain poorly understood. This study aimed to identify systemic lipidomic signatures characterizing the pathophysiological heterogeneity of these conditions. METHODS We conducted a cross-sectional lipidomic analysis of peripheral plasma from age- and sex-matched patients with COPD (n = 25) and PF (n = 27, serum KL-6 >1000 U/mL) using liquid chromatography-tandem mass spectrometry. RESULTS Twenty-eight lipid species were significantly differentially expressed. COPD was characterized by systemic ceramide depletion and enhanced lysophosphatidylethanolamine - phosphatidylethanolamine - phosphatidylserine (LPE-PE-PS) metabolic cycling, reflecting distinct membrane remodeling processes compared to PF. The correlation between lysophosphatidic acid (LPA) 16:0 levels and forced expiratory volume at 1 s/forced vital capacity (FEV1/FVC) was divergent: inverse in COPD and positive in PF. This metabolic mirror effect highlights how plasma lipid signatures reflect contrasting mechanical environments, airflow obstruction in COPD versus radial traction-induced airway patency in PF. CONCLUSIONS These findings suggest that systemic lipidomic profiles provide a molecular framework for identifying disease-specific treatable traits offering a foundation for advancing personalized clinical management in chronic respiratory diseases. TRIAL REGISTRATION Registry for UMIN, Lipidomic analysis on plasma in idiopathic pulmonary fibrosis patients. Trial registry number, UMIN000020872.