Identification and mechanistic study of metabolic-immune subtypes in COPD based on integrated transcriptomic-metabolomic analysis

This study aimed to characterize immune cell metabolic alterations and their regulatory mechanisms in chronic obstructive pulmonary disease (COPD), and to identify metabolism-related immune subtypes associated with lung dysfunction to support immunometabolic classification and targeted therapeutic strategies. Public transcriptomic and single-cell RNA sequencing datasets were integrated to identify key metabolic genes, classify COPD patients into molecular subtypes, and characterize immune cell metabolic profiles and regulatory networks. Untargeted serum metabolomics was performed to identify differential metabolites. A cigarette smoke-induced COPD mouse model was established, and multiple molecular and histological experiments were performed for validation. We identified 27 core metabolic genes and classified COPD patients into two subtypes. Subtype C1 was characterized by poorer lung function and higher infiltration of innate immune cells, with enrichment of SPP1⁺ macrophages exhibiting increased glycolytic and lipid metabolic activity. Transcription factors MITF, TCF7L2, and BHLHE41 were identified as predicted upstream regulators of the metabolic reprogramming observed in these cells, which showed increased interactions with CD8⁺ Tem and NK cells. Serum lactate and succinate levels were significantly upregulated in patients with COPD. Animal experiments further confirmed increased proportion of SPP1⁺ macrophages, elevated expression of metabolic genes, and increased levels of pro-inflammatory cytokines in COPD mice. COPD exhibits distinct immune heterogeneity characterized by altered cellular metabolism. SPP1⁺ macrophages represent a prominent myeloid subset closely associated with metabolic disorders and lung injury. These results provide a basis for immunometabolic subtyping of COPD and may inform the development of targeted therapeutic strategies.