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.