Aug 2026· Metabolomics· Vol 22· 0 citations· 60 references
Medicine
TL;DR
Alterations in metabolomic profiles of COPD and IPF suggested shared dysregulation of several lipids, however, some metabolites pointed to disease-specific differences.
Abstract
Chronic Obstructive Pulmonary disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are chronic pulmonary disorders with distinct pathologies but shared risk factors. Metabolomics may provide insights into mechanisms. To identify metabolites associated with COPD and IPF, and to characterize shared and disease-specific signatures. Plasma metabolomic profiling was conducted in the Lung Tissue Research Consortium (LTRC). Logistic regression identified metabolites associated with COPD and IPF, and results were replicated in an external cohort, COPDGene. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to explore disease-associated metabolite modules. We further evaluated relationships between significant metabolites and risk genes of interest. Of 1131 metabolites in LTRC, 246 (21.8%) differed between COPD and controls, and 136 (12.0%) between IPF and controls (FDR < 0.05). Among 80 shared significant metabolites in COPD and IPF, 77 showed concordant directions of effect. Shared metabolomic changes included reduced levels of steroids, triglycerides, diglycerides, phosphatidylcholines, and increased levels of carnitines. In contrast, polyunsaturated fatty acids, nicotine, and thyroxine metabolites differed between COPD and IPF; these findings were further explored by the WGCNA. External replication was performed for 120 metabolites measured in both cohorts, of which 49 (40.8%) replicated in COPD vs. control. In exploratory analyses leveraging quantitative imaging abnormalities (QIA) as a surrogate for IPF; only 4 (3.3%) metabolites replicated in the QIA vs. control model, and only 9 (7.5%) for COPD vs. QIA. Alterations in metabolomic profiles of COPD and IPF suggested shared dysregulation of several lipids. However, some metabolites pointed to disease-specific differences.
Untargeted metabolomics has revealed significant systemic metabolic dysregulation in ILD and the biomarkers and “metabolic-immune-endocrine” interaction patterns identified offer potential leads for early diagnosis and targeted treatment, which require validation in larger cohorts.
Lu Liu, Xinyi Wang, Jinling Xiao et al.· Frontiers in Medicine· 0 citations
OBJECTIVES
People living with HIV (PLWH) carry increased risk of chronic obstructive pulmonary disease (COPD), yet the underlying mechanisms remain poorly understood. We investigated whether systemic inflammatory profiles differ between PLWH with and without COPD.
METHODS
We analyzed serum samples from 87 PLWH: 38 with COPD and 49 without COPD, matched for age and sex. Inflammatory proteins were measured using the Olink Target 96 Inflammation panel. Modules of co-varying analytes were identified using CytoMod, and associations with clinical features were tested. Key findings were validated using ELISA. A replication analysis was conducted in 158 samples from an independent cohort.
RESULTS
PLWH with COPD showed significantly elevated inflammatory markers. CytoMod analysis identified five modules when adjusting for background levels. Two modules were significantly associated with COPD, and comprised molecules involved in tissue damage and repair. Individual molecules including PD-L1, FGF-23, IL6, and others were significantly dysregulated. ELISA validation confirmed significantly elevated levels of IL-10RB, PD-L1, M-CSF, and IL-6 in PLWH-COPD. Key analytes and directional effects were confirmed in an independent cohort.
CONCLUSIONS
PLWH with COPD exhibit distinct inflammatory signatures characterized by enhanced tissue damage, immune activation, and dysregulated repair mechanisms, providing insights into HIV-related COPD.
Lennart Riemann, Lena Böger, Carina Dahl et al.· Journal of Infection· 0 citations
Background Early diagnosis of chronic obstructive pulmonary disease (COPD) remains challenging due to the limited sensitivity of spirometry and imaging in early-stage disease and the lack of reliable blood-based biomarkers. COPD is increasingly recognized as a heterogeneous disorder driven by coordinated immune dysregulation and airway structural remodeling; however, clinically applicable molecular signatures that capture these processes are still lacking. Objectives To identify and validate a blood-based diagnostic signature for COPD and to explore the underlying immune and structural remodeling mechanisms. Design A multi-stage integrative study combining retrospective bioinformatics analysis with prospective experimental validation. Methods Public lung transcriptomic datasets were used to identify COPD-associated candidate genes through differential expression, co-expression network, and machine-learning analyses. Candidate genes were validated by RT-qPCR in peripheral blood samples from stable COPD patients and healthy controls. Exploratory immune, single-cell, virtual perturbation, and molecular simulation analyses were performed to assess potential biological relevance. Results Four lung-derived candidate genes, AC079767.4, CEP55, EMR3, and ATP6V0D2, were identified. In peripheral blood validation, CEP55 and ATP6V0D2 showed the strongest diagnostic performance, whereas AC079767.4 showed limited blood-based discriminatory ability. Functional and immune analyses suggested that these genes may be associated with intracellular pH regulation, vesicular acidification, cytokinesis, immune imbalance, and inflammatory pathways. Single-cell analysis indicated that CEP55 was mainly enriched in epithelial, endothelial, and smooth muscle cells, whereas ATP6V0D2 was enriched in macrophages and monocytes. Virtual perturbation and molecular simulation analyses provided hypothesis-generating evidence for possible involvement in antigen presentation, T-helper-cell-related pathways, and ligand–target interactions. Conclusion This study identified four lung-derived COPD-associated candidate genes through integrative transcriptomic, network, and machine-learning analyses. Among them, CEP55 and ATP6V0D2 showed the strongest peripheral-blood diagnostic performance and biological plausibility, supporting their prioritization as candidate circulating biomarkers for further validation. Exploratory docking and MD simulations suggested possible ligand–target interactions involving CEP55 and ATP6V0D2, but these computational findings require experimental pharmacological validation before any therapeutic relevance can be inferred.
Wenbo Du, Yukun Wang, Xiang Li et al.· Therapeutic Advances in Resp...· 0 citations
The findings reveal coordinated dysregulation of mitochondrial energy metabolism, redox homeostasis, and lipid remodeling in COPD, highlighting the interconnected roles of metabolic reprogramming, oxidative stress, and inflammation in disease pathophysiology.
Hangming Xiong, Yingying Xue, Xiaojing Zhang et al.· Journal of Proteomics· 0 citations
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.
Kayako Suda, Y. Shimizu, Y. Horibata et al.· Respiratory Investigation· 0 citations
INTRODUCTION/BACKGROUND
Chronic obstructive pulmonary disease (COPD) is associated with increased lung adenocarcinoma (LUAD) risk, but the cellular and molecular programs linking chronic inflammatory remodeling to malignancy remain incompletely defined. Transcriptomic overlap alone cannot distinguish potential upstream contributors from downstream remodeling events.
MATERIALS AND METHODS
We integrated lung single-cell RNA sequencing datasets from COPD (GSE196638) and LUAD (GSE131907) with two-sample Mendelian randomization (MR) to prioritize shared genes with supportive genetic evidence. Cell-type-resolved transcriptional signatures were identified and intersected across diseases. Shared candidates were screened using cis-eQTL instruments from eQTLGen and GWAS summary statistics for COPD and LUAD. FAM174B protein expression was further examined using publicly available Human Protein Atlas immunohistochemistry data with the anti-FAM174B antibody HPA015306.
RESULTS
Intersection analysis identified 484 shared genes enriched in cytoskeletal organization and cell-substrate adhesion. Exploratory MR screening prioritized FAM174B as a leading shared candidate with nominal risk-increasing estimates for COPD (OR = 1.094, 95% CI: 1.009-1.186) and LUAD (OR = 1.196, 95% CI: 1.026-1.395). These estimates should be interpreted as supportive genetic prioritization rather than definitive causal proof, because formal multiple-testing correction and colocalization were not performed. Human Protein Atlas immunohistochemistry showed low FAM174B staining in normal lung tissue and higher staining in lung adenocarcinoma tissue, supporting disease-associated protein expression but not establishing the cellular source within tumor tissue. Single-cell analyses localized FAM174B expression to immune compartments, including monocytes, and ligand-receptor inference suggested LUAD-associated monocyte signaling shifts involving adhesion- and matrix-associated pathways.
DISCUSSION
These findings suggest that FAM174B-associated monocyte remodeling may represent a candidate biological context linking COPD-related inflammatory remodeling with LUAD-associated tumor microenvironmental change. However, the evidence remains hypothesis-generating, as the MR analysis was exploratory, the single-cell comparisons were not donor-aware, and protein-level evidence was based on public representative immunohistochemistry images.
CONCLUSION
This integrative analysis prioritizes FAM174B as a shared COPD-LUAD candidate with supportive genetic, single-cell, and protein-level evidence. Experimental validation, colocalization, donor-aware single-cell analysis, and cell-type-resolved protein confirmation are needed before a causal or therapeutic role can be established.
Hailin Chen, Xuefei Yang, Yufeng Zhao et al.· Current Cancer Drug Targets· 0 citations
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