Fibroblast-derived Mimecan deficiency drives COPD pathogenesis via Wnt5a-mediated alveolar epithelial cell dysfunction

The molecular mechanisms driving emphysema in Chronic Obstructive Pulmonary Disease (COPD) remain incompletely understood. Mimecan, a small leucine-rich proteoglycan, is implicated in tissue homeostasis, but its role in COPD is unknown. This study aimed to investigate the function and underlying mechanism of Mimecan in the pathogenesis of COPD emphysema. We analyzed Mimecan expression in public datasets of COPD patients and in cigarette smoke (CS)-induced mouse models. The role of Mimecan was assessed using Mimecan-knockout (Mimecan -/- ) mice exposed to CS. Phenotypic changes were evaluated through lung function tests, histological analysis, and assessments of apoptosis, proliferation, and oxidative stress. Single-cell RNA sequencing (scRNA-seq) was performed on lung tissues to identify downstream pathways. Mechanistic validation involved in vitro cell culture systems and in vivo therapeutic intervention using a Wnt5a neutralizing antibody. Mimecan expression was significantly downregulated in the lungs of COPD patients and CS-exposed mice, primarily localized to fibroblasts, and positively correlated with lung function. Mimecan -/- mice exhibited spontaneous emphysema-like changes, characterized by impaired lung function, increased alveolar destruction, apoptosis, and oxidative stress, alongside reduced epithelial proliferation and decreased alveolar epithelial cell (AEC) number. Mechanistically, scRNA-seq and subsequent validation revealed that Mimecan deficiency in fibroblasts led to an upregulation of Wnt5a. In vitro, Wnt5a inhibited AEC proliferation and differentiation, while conditioned medium from Mimecan-deficient fibroblasts induced epithelial apoptosis, an effect reversible by a Wnt5a inhibitor. Crucially, in vivo administration of a Wnt5a neutralizing antibody significantly ameliorated the emphysematous phenotype, improved lung function, and restored alveolar epithelial cell homeostasis in Mimecan -/- mice. Our findings demonstrate that fibroblast-derived Mimecan protects against emphysema by restraining Wnt5a secretion. Loss of Mimecan upregulates Wnt5a, which in turn induces alveolar epithelial cell apoptosis and impairs regenerative capacity. This study identifies the Mimecan–Wnt5a axis as a novel regulatory pathway in emphysema pathogenesis and provides preclinical proof-of-concept that targeting Wnt5a may represent a promising therapeutic strategy for COPD.