Background: Acute exacerbations of COPD (AECOPD) involve poorly characterized airway host responses. Integrating sputum proteomics with radiomics may reveal underlying molecular heterogeneity and identify clinically relevant biomarkers. Methods: 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 were used to define molecular endotypes. Proteomic modules were correlated with quantitative chest CT radiomic features including ground-glass opacity (GGO), consolidation, and parenchymal heterogeneity. Results: We identified two major endotypes in AECOPD. The ciliary-enriched endotype showed coordinated upregulation of ciliary proteins (e.g., PCM1, CFAP58, TMEM231) and was associated with elevated MUC5AC. In contrast, the keratinization-dominant endotype was characterized by epithelial repair programs. Radiomic analysis revealed that the keratinization-dominant module positively correlated with GGO volume, consolidation burden, and parenchymal heterogeneity, while the ciliary module was linked to more homogeneous lung parenchyma. Across the AECOPD cohort, mucosal immunoglobulins, particularly IgA-related proteins, were markedly depleted and served as strong independent predictors of protection against future severe exacerbations, outperforming traditional clinical indicators. Conclusion: AECOPD is molecularly heterogeneous, featuring a ciliary-enriched endotype with paradoxical ciliary activation and a keratinization-dominant endotype associated with greater inflammatory burden on imaging. Baseline immunoglobulin levels provide powerful prognostic information. These findings offer a new framework for endotype-driven precision management in COPD.