Targeting Elastin‐Derived Peptides Reverses Alveolar Epithelial Dysfunction in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar destruction and defective regeneration, yet the matrix-derived factors contributing to this process remain poorly defined. We investigated the role of elastin-derived peptides (EDPs), bioactive fragments generated during cigarette smoke (CS)-induced elastin degradation, in alveolar epithelial dysfunction. In lung tissues from patients with COPD and in CS-exposed mice, elevated levels of EDPs were associated with elastic fiber disruption and impaired alveolar type 2 (AT2)-to-alveolar type 1 (AT1) differentiation. These observations were supported by histological analyses, single-cell transcriptomic profiling, and organoid-based functional assays. In mouse and human alveolar organoids, CS extract and EDPs each suppressed organoid growth and impaired AT2-to-AT1 differentiation. Mechanistically, EDPs exposure was associated with activation of TLR4/NF-κB signaling, and reduced β-catenin activity, whereas pharmacological inhibition of TLR4 partially restored alveolar epithelial differentiation. Notably, the EDPs-neutralizing agent TB partially rescued AT2-to-AT1 differentiation in organoids and alleviated emphysematous injury in vivo. Together, these findings identify EDPs as an important matrix-derived mediator of alveolar regenerative failure in COPD and support further evaluation of EDP-targeted intervention as a potential strategy for promoting alveolar repair.