Cebpb/JAK2/STAT3 signaling pathway mediated M1 macrophage polarization and metabolic rewiring drive COPD pathogenesis.

Abstract

Chronic obstructive pulmonary disease (COPD) is asyndrome characterized by airflow limitation, and its pathogenesis is not fully understood. This study intends to conduct a systematic analysis of the key cellular and metabolic remodeling mechanisms involved in the occurrence and development of COPD. A murine COPD model was established and analyzed by histopathology, molecular assays, scRNA-seq, and targeted metabolomics to investigate pulmonary inflammation, microenvironment changes, cellular composition, and signaling dysregulation. Furthermore, CCAAT enhancer-binding protein β (Cebpb) was knocked down in M1-polarized macrophages to assess its role in gene expression and energy metabolism reprogramming. The results showed that pulmonary inflammation was increased in COPD mice, with elevated inflammatory cell infiltration, pro-inflammatory cytokine upregulation, and enhanced M1 macrophage polarization. Specifically, scRNA-seq revealed immune cell landscape remodeling, with T cells as central intercellular mediators. Additionally, macrophage differentially expressed genes were enriched in energy metabolism pathways, including ribosome and oxidative phosphorylation. Moreover, targeted metabolomics demonstrated substantial metabolic alterations in lung tissues and macrophages, particularly in ABC transporters, amino acid metabolism, and the tricarboxylic acid (TCA) cycle. Mechanistically, the Cebpb/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) axis was strongly activated in COPD lungs and M1-polarized macrophages. Functionally, Cebpb silencing suppressed this pathway activity, macrophage invasion, and M1 polarization, whereas exogenous JAK2/STAT3 activation reversed these effects. Consistently, RNA-seq confirmed that Cebpb regulates macrophage gene expression and metabolic profiles. In conclusion, the Cebpb/JAK2/STAT3 pathway is activated in COPD and promotes progression by driving M1 macrophage polarization and orchestrating downstream metabolic reprogramming.