Micropeptide PEP1695 mitigates lung injury in COPD mice by inhibiting epithelial-mesenchymal transition of type II alveolar epithelial cells.

Micropeptides encoded by small open reading frames (smORFs) within long noncoding RNAs (lncRNAs) have emerged as important regulators of various biological processes. However, whether micropeptides mitigate lung tissue damage in chronic obstructive pulmonary disease (COPD) remains poorly understood. In COPD, the epithelial-mesenchymal transition (EMT) of type II alveolar epithelial (ATII) cells plays a crucial role in lung injury, contributing to fibrosis and airway remodeling. Modulating EMT could offer a promising therapeutic strategy for COPD. In this study, we identified a micropeptide, PEP1695, encoded by lncRNA-MSTRG.1695.1, as a key regulator of EMT in mouse ATII cells. Mechanistic investigations revealed that PEP1695 inhibits EMT in ATII cells by binding to p38-MAPK. Using a COPD mouse model, we observed a significant reduction in PEP1695 expression in ATII cells, administration of PEP1695 effectively improved lung function and reduced inflammation, highlighting its potential as a novel targeted biologic therapy for COPD. Moreover, preliminarily serum analysis from COPD patients revealed a positive correlation between PEP1695 homolog levels and lung function. PEP1695 represents a promising therapeutic target for lung injury in COPD and has preliminarily shown potential as a serum marker for the evaluation of early fibrosis in COPD patients.