Identifying Therapeutic Targets and Biomarkers for COPD: Insights from a Mouse Proteomic Study

Xishuai Wang ^1,2* Cong Liu ² Ruining Liang ³ Xin Hu ⁴ Dan Xu ⁵ Yuehui Zhou ¹ Xiliang Kong ¹ Yun Wang ⁶ Lunan Zhao ^1* Weina Niu ⁷ Chao Yi ¹ fugao Jiang ^1*

• ¹ Qufu Normal University, Qufu, Shandong Province, China
• ² Beijing Normal University, Beijing, China
• ³ Xinjiang Medical University, Ürümqi, Xinjiang Uyghur Region, China
• ⁴ Nanjing Sport Institute, Nanjing University, Nanjing, Jiangsu Province, China
• ⁵ People’s Education Press, Beijing, China
• ⁶ Taiyuan University, Taiyuan, Shaanxi, China
• ⁷ Qilu Institute of Technology (QIT), Jinan, Shandong Province, China

Background: In chronic obstructive pulmonary disease (COPD) patients, protein expression changes significantly, which may be closely linked to the pathogenesis of this disease. Further research is needed to investigate how these changes affect COPD development and identify potential therapeutic targets.Methods: COPD was induced by cigarette smoke (CS) and lipopolysaccharide (LPS) exposure. We quantified histopathology, lung function indicators, cytokine profiles, oxidative stress markers, and metabolic parameters and performed proteomic profiling.Results: CS and LPS exposure led to decreased lung function, emphysema, pulmonary inflammation, oxidative stress, metabolic dysfunction, and proteomic reprogramming. GO and KEGG analyses revealed that the differentially abundant proteins (DAPs) were significantly enriched in immune responses, inflammatory responses, immune cell chemotaxis, energy metabolism, apoptosis, NF-κB, immunoglobulin (Ig)A, interferon, major histocompatibility complex (MHC), and diabetes mellitus. Protein‒protein interaction analyses identified Ras-related C3 botulinum toxin substrate 2 (RAC2), Caspase 1, MHC I, and MHC II as central nodes. CS and LPS induced neutrophil accumulation by increasing RAC2 expression and apoptosis via the TRAIL/FADD/CASP8 pathway; upregulated BCR, IgA, IgD, IgE, IgG, and IgM expression through B-cell receptor signaling; activated NF-κB via CD14-TLR4-MYD88 signaling; and promoted β-cell apoptosis by increasing MHC class I, MHC class II, and granzyme B (GZMB) expression. The qRT‒PCR and proteomic results were consistent.Conclusions: Our study revealed crucial roles for IgA, RAC2, MHC molecules, and key inflammatory and apoptotic pathways in COPD. Adiponectin, GLUT4, MHC I, MHC II, and GZMB bridge the connection between COPD and metabolic dysfunction. Targeting these proteins and pathways may provide new therapeutic strategies for managing COPD.