Abstract

Background Epithelial-mesenchymal transition (EMT) represents a key pathological mechanism underlying airway remodeling in asthma. However, the role of the circadian clock component PER2 in asthma-associated airway remodeling remains unclear. Objective This study aimed to investigate the role of the circadian clock component PER2 in the pathogenesis of EMT in asthma and to elucidate the underlying molecular mechanism. Methods PER2 expression on airway epithelial and association between of PER2 and lung function were determined using data from public databases. The wild-type (WT) and Per2 knockout ( Per2 ⁻/⁻ ) mice was induced ovalbumin (OVA) to establish asthma model. Airway hyperresponsiveness (AHR), inflammation, mucus production, fibrosis, and EMT markers were assessed. Human bronchial epithelial cells (BEAS-2B) were stimulated with TGF-β1 to induce EMT, followed by PER2 overexpression. RNA sequencing, Western blot, immunofluorescence, and functional migration assays were employed. The Wnt/β-catenin agonist SKL2001 was used to rescue the phenotype. The role of melatonin was also investigated in vivo. Results Bioinformatic and clinical data identified PER2 as a key downregulated circadian gene in asthma, correlating with impaired lung function. Per2 ⁻/⁻ mice exposed to OVA exhibited exacerbated AHR, airway inflammation, mucus hypersecretion, subepithelial fibrosis, and enhanced EMT markers compared to WT mice exposed to OVA. RNA-seq and pathway analysis revealed that PER2 deficiency activated the Wnt/β-catenin pathway. In vitro, TGF-β1 downregulated PER2 expression. Overexpression of PER2 in cells suppressed TGF-β1-induced EMT, migration, and inhibited Wnt/β-catenin signaling activation. The protective effects of PER2 were partly reversed by the β-catenin agonist SKL2001. Finally, melatonin alleviated OVA-induced EMT by upregulating the PER2. Conclusion This study demonstrates that the circadian clock component PER2 plays a critical protective role in