Unraveling COPD pathogenesis: a multi-omics approach to identify metabolites and genetic links.

Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder driven by genetic, environmental, and metabolic factors. This study aims to elucidate the causal role of metabolites in COPD pathogenesis and identify novel therapeutic targets through a multi-omics approach coupled with experimental validation. We performed two-sample Mendelian randomization (MR) on 1,400 metabolites using genetic data from European-ancestry cohorts. Causal candidates were refined using stringent conditional colocalization (SuSiE, PP4 > 0.8) to exclude pleiotropic confounders. Pathway enrichment and protein-protein interaction (PPI) analyses were conducted to identify key mechanisms. Findings were validated in external transcriptomic datasets (GEO) and an in vitro COPD model using cigarette smoke extract (CSE)-induced human bronchial epithelial cells (BEAS-2B/16HBE). The regulatory effects of the COPD drug Salbutamol on the identified metabolic targets were assessed via qRT-PCR and Western Blot. Initial MR identified six COPD-associated metabolites, but stringent colocalization confirmed a shared causal etiology for only two: Carnitine C14 and 3-hydroxyoleoylcarnitine. The remaining candidates were excluded due to confounding (high PP3). Pathway analysis highlighted fatty acid metabolism, implicating the rate-limiting enzymes ACACA and ACACB. Transcriptomic validation in human tissues confirmed the upregulation of ACACA/ACACB and downregulation of ADRB2 in COPD. In in vitro experiments, CSE exposure inhibited the phosphorylation of ACACA, promoting metabolic dysregulation. Crucially, Salbutamol treatment restored ACACA phosphorylation via the ADRB2 signaling axis, reversing the lipid metabolic dysregulation. This study identifies Carnitine C14 and 3-hydroxyoleoylcarnitine as robust causal biomarkers for COPD. We experimentally demonstrated that the bronchodilator Salbutamol exerts a non-canonical therapeutic effect by restoring fatty acid metabolic homeostasis through the ADRB2-ACACA axis. These findings propose a novel metabolic mechanism for existing therapies and highlight lipid metabolism as a promising target for intervention.