PER2, a circadian clock component, is identified as a key downregulated gene in asthma, correlating with impaired lung function.
Mice lacking PER2 exhibited exacerbated airway hyperresponsiveness, inflammation, mucus production, and fibrosis when exposed to an asthma-inducing agent.
Deficiency of PER2 activated the , which is associated with enhanced (EMT) markers.
In vitro experiments showed that overexpression of PER2 decreased TGF-β1-induced EMT and inhibited cell migration.
Melatonin was found to alleviate EMT induced by an asthma model by increasing PER2 expression.
These findings suggest that targeting PER2 may offer a novel therapeutic approach for managing airway remodeling in asthma.
Simplified
BACKGROUND: (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: expression on airway epithelial and association between ofand lung function were determined using data from public databases. The wild-type (WT) andknockout () 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. PER2PER2Per2Per2 ⁻/⁻
RESULTS: Bioinformatic and clinical data identifiedas a key downregulated circadian gene in asthma, correlating with impaired lung function.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 thatdeficiency 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. PER2Per2PER2 ⁻/⁻
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 . Furthermore, melatonin exerts its therapeutic effects by upregulating PER2. Targeting the PER2 may represent a novel therapeutic strategy for mitigating airway remodeling in asthma.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03522-8.
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Declarations. Ethics approval and consent to participate: Animal experimental procedures were approved by the Animal Experimentation Ethics Committee of China-Japan Friendship Hospital (No. ZRDWLL240062). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
