B15-01 Metformin Mitigates Emphysema by Favoring Plasmalogen Production in COPD Patients

Abstract Background Chronic Obstructive Pulmonary Disease (COPD) is characterized by profound metabolic derangements, including impaired mitochondrial function and altered lipid homeostasis in alveolar epithelial cells. We previously demonstrated that metformin, a widely used antidiabetic agent, slows emphysema progression and preserves alveolar structure in COPD, suggesting it may protect against COPD-associated metabolic decline. Here, we investigated whether metformin restores the altered lipid and mitochondrial metabolism characteristic of COPD. Methods We integrated plasma metabolomics from the COPDGene cohort with human lung tissue analyses from metformin users and non-users to identify lipid pathways modulated by metformin. Lung tissues underwent histological evaluation, untargeted metabolomics, and spatial lipidomics. In vivo, wild-type mice were chronically exposed to cigarette smoke (CS) for six months with or without 1% metformin chow. Ex vivo, human precision-cut lung slices (PCLS) and murine alveolar type 2 (AT2) organoids were treated with metformin ± cigarette smoke extract (CSE), followed by bulk RNA sequencing to characterize transcriptional and metabolic responses. Results Spatial lipidomics identified 24 metabolites significantly enriched in metformin users, including mono- and polyunsaturated phosphatidylserines (PS), phosphatidic acids (PA), phosphatidylinositols (PI), lysophosphatidic acids (LysoPA), lysophosphatidylethanolamines (LysoPE), and antioxidant plasmalogens such as PE(P-34:0)/LPE(34:1)—lipid species typically depleted in COPD. Conversely, metformin users showed reduced levels of pro-inflammatory sphingomyelins SM(d18:1/24:0), SM(d18:0/24:1-OH), SM(d18:1/26:0), restoring a lipid profile closer to that of healthy controls. Pathway enrichment analyses revealed reactivation of phosphatidylcholine and phosphatidylethanolamine synthesis and normalization of lipid salvage and remodeling pathways disrupted in COPD. In mouse lungs, metformin reversed CS-induced suppression of surfactant genes and restored lamellar body formation. AT2 organoids treated with metformin exhibited upregulation of oxidative phosphorylation (OXPHOS), TCA cycle, and fatty acid β-oxidation genes, while human PCLS demonstrated increased mitochondrial complex I expression, consistent with restored mitochondrial function. Conclusions Metformin effectively reverses the disordered lipid and mitochondrial metabolism that characterizes COPD. By replenishing phospholipids essential for alveolar membrane integrity, enhancing antioxidant plasmalogens, and restoring mitochondrial bioenergetics, metformin re-establishes a metabolic state supportive of AT2 cell survival and surfactant production. These findings reveal metformin as a potent modulator of alveolar metabolism that counteracts COPD-associated metabolic decline, providing a strong rationale for its repurposing as a disease-modifying therapy in emphysema. This abstract is funded by: R01 HL149744, R01 HL171622.