Notch Signaling Pathway Regulates Ozone-Induced Lung Circadian Rhythm Disruption
2025
Xinyu Zhang | Xiaotong Jian | Xinyi Miao | Yangyang Jia
Background: Ozone (O3) pollution disrupts pulmonary circadian rhythms, yet the molecular mechanisms remain elusive. The Notch signaling pathway, critical for lung homeostasis, may crosstalk with the circadian clock system. Objective: This study elucidates the role of the Notch signaling pathway in O3-induced lung circadian rhythm disruption. Methods: C57BL/6J mice were acutely exposed to O3 (1.0 ppm, 3 h). Lung tissues were collected 24 h post exposure. Transcriptome sequencing coupled with GSEA identified dysregulated pathways: IHC and RT-qPCR validated core genes: GEO dataset (GSE58244) reanalysis assessed Notch3/4 knockout effects. Results: O3 activated Notch signaling (NES = 1.85, FDR = 0.034) and disrupted the circadian pathway (NES = 1.84, FDR = 0.029), downregulating Bmal1 while upregulating Per2/3 and Notch3/4 (p <: 0.05). Strong correlations (r >: 0.8) existed between core genes of both pathways. Notch3/4 knockout exacerbated circadian disruption in a time-dependent manner upon O3 exposure. Conclusion: O3 induces lung circadian disruption via Notch3/4 activation, which provides novel mechanistic insights into pollutant-induced lung injury.
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