The circadian clock component PER2 deficiency aggravates airway epithelial remodeling through Wnt/β-catenin signaling pathway

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 inhibiting airway remodeling in asthma by suppressing EMT through the Wnt/β-catenin signaling pathway. Furthermore, melatonin exerts its therapeutic effects by upregulating PER2. Targeting the PER2 may represent a novel therapeutic strategy for mitigating airway remodeling in asthma.