Melatonin Ameliorates Circadian Disruption‐Associated Dry Eye via Modulation of BMAL1‐REV‐ERBα‐IL‐17 Axis and Ocular Surface Microbiota Homeostasis

The association between modern lifestyle factors and dry eye disease (DED) pathogenesis has garnered increasing scientific attention. Emerging evidence implicates circadian disruption-a prevalent consequence of contemporary living patterns-as a significant yet not fully clarified pathogenic factor in DED development. To address this knowledge gap, we developed a circadian disruption mouse model using chronic jet lag exposure. Mice subjected to chronic jet lag exhibited conjunctival clock gene dysregulation and upregulated pro-inflammatory mediators, such as TNF-α, IL-6, and IL-17. Transcriptomic profiling demonstrated marked activation of IL-17-mediated inflammatory pathways within the conjunctival tissue. Therapeutic IL-17 neutralization substantially attenuated ocular surface inflammation, improved corneal epithelial integrity, and decreased apoptotic cell density in circadian disruption-induced dry eye mouse model. Moreover, REV-ERBα agonism potently suppressed IL-17 transcription, whereas BMAL1 deficiency exacerbated IL-17-driven inflammatory responses through REV-ERBα downregulation. Chronic jet lag additionally induced ocular surface microbiota dysbiosis, characterized by Firmicutes overproliferation. Melatonin administration effectively suppressed conjunctival IL-17 expression through BMAL1-REV-ERBα pathway activation while reducing the relative abundance of Firmicutes to restore ocular surface microbiota balance. Our study reveals that circadian disruption induces ocular surface inflammation through the BMAL1-REV-ERBα-IL-17 signaling axis and exacerbates dysbiosis of the ocular surface microbiota. Melatonin mitigates these pathological alterations via dual-directional modulation of circadian-immune signaling crosstalk and restoration of microbiota balance. Importantly, this study establishes melatonin as a multifaceted therapeutic agent for combating lifestyle-associated DED, while elucidating the underlying mechanisms governing circadian rhythm-microbiome axis dynamics in ocular surface pathogenesis.