Early-life cigarette smoke exposure predisposes to COPD by suppressing the HAS2-TGF-B1-MAPK axis in lung fibroblasts

Background Early‐life exposure to environmental tobacco smoke (ETS) increases the risk of developing COPD in adulthood, but the underlying mechanisms remain poorly understood. Using comparative cigarette smoke (CS) exposure in neonatal and adult mice, we show that early‐life CS produces fundamentally different pathology from adult exposure. Adult mice develop classic COPD features—airway wall thickening and increased collagen deposition—whereas neonatal mice exhibit progressive alveolar enlargement, reduced interstitial collagen, and impaired lung function. These structural deficits persist after CS withdrawal. Transcriptomic and protein analyses reveal that neonatal CS exposure suppresses the TGF-β1-MAPK axis, with decreased expression of fibroblast markers but not epithelial markers, identifying fibroblasts as the primary targets. In vitro, cigarette smoke extract directly downregulates PDGFRα, FN1, COL1, and α‐SMA in lung fibroblasts, effects that are dose‐dependently rescued by exogenous TGF-β1. Mechanistically, neonatal smoke exposure suppresses the TGFβ1-MAPK signaling axis in lung fibroblasts. Single-cell RNA-seq data from COPD and IPF patients confirmed that MAPK activity in COPD fibroblasts positively correlates with extracellular matrix and collagen signatures, and that the HAS2-TGFβ1-MAPK signaling axis regulates fibrosis through a uniquely inflammation-driven mechanism. Together, these findings establish that early-life CS exposure causes irreversible alveolar simplification by suppressing the TGF-β1-MAPK axis in lung fibroblasts, linking childhood ETS exposure to COPD susceptibility and identifying HAS2, a marker of myofibroblasts, as a potential therapeutic target. Methods Male BALB/c mice (7–8 weeks old) and neonatal BALB/c mice were exposed to cigarette smoke (CS), with eight animals per group. Model validation was performed using histopathological staining, pulmonary function testing, and computed tomography (CT) imaging. Transcriptomic profiling of lung tissues from CS-exposed neonatal mice was conducted using RNA sequencing and integrated with publicly available human and murine COPD datasets. Based on bioinformatic findings, lung fibroblast cell lines and primary fibroblasts were used for phenotypic and signaling pathway validation via Western blot analysis.