Ciliary-enriched and keratinization-dominant endotypes drive molecular heterogeneity in AECOPD

Acute exacerbations of COPD (AECOPD) exhibit poorly characterized airway host responses. Integrating sputum proteomics with radiomics may reveal underlying molecular heterogeneity and identify clinically relevant biomarkers. We performed deep proteomic profiling on induced sputum from patients with AECOPD ( n = 35), stable COPD ( n = 19), and healthy controls ( n = 15). Weighted gene co-expression network analysis (WGCNA) and consensus clustering defined molecular endotypes. Proteomic modules were correlated with quantitative chest CT radiomic features, including ground-glass opacity (GGO), consolidation, and parenchymal heterogeneity. We identified distinct molecular endotypes in AECOPD. The ciliary-enriched endotype showed upregulated ciliary proteins (e.g., PCM1, CFAP58) and elevated MUC5AC, reflecting preserved epithelial integrity. Conversely, the keratinization-dominant endotype featured epithelial repair programs. Radiomics revealed the keratinization module positively correlated with GGO volume, consolidation, and parenchymal heterogeneity, whereas the ciliary module linked to homogeneous lung parenchyma. Additionally, mucosal immunoglobulins exhibited dysregulation and consumptive depletion during AECOPD. Notably, a composite prognostic risk score derived from these immunoglobulin-related features independently predicted future severe exacerbations, significantly outperforming the traditional clinical predictor of prior exacerbation history. AECOPD is molecularly heterogeneous, featuring a ciliary-enriched endotype reflecting preserved epithelial integrity and a keratinization-dominant endotype associated with greater radiographic inflammatory burden. Furthermore, baseline immunoglobulin levels provide powerful prognostic information. These findings offer a novel framework for endotype-driven precision management in COPD.