Nobiletin restores corneal circadian transcriptome organization and mitigates ocular surface pathology in high-fructose-induced metabolic dysfunction.

PURPOSE: Excess fructose intake promotes metabolic syndrome and disrupts peripheral circadian programs, but its effects on the ocular surface are unclear. This study tested whether a high-fructose diet reprograms the corneal circadian transcriptome and whether the clock-modulating flavonoid nobiletin provides protection.

METHODS

Male C57BL/6J mice were fed a high-fructose diet for 6 weeks, with nobiletin administered during weeks 5-6. Corneas were collected every 3 h over a 24-h period at eight Zeitgeber time (ZT) points for time-resolved RNA sequencing (RNA-seq) and rhythmicity analysis. Histology, immunostaining, and corneal sensitivity testing were performed to assess structural and functional changes.

RESULTS

High-fructose feeding induced systemic metabolic dysfunction and extensively remodeled the corneal circadian transcriptome, increasing the number of rhythmic genes from 1448 to 2704 with pronounced phase dispersion. Altered pathways were associated with cell adhesion, immune regulation, and neuronal transmission. These molecular changes were accompanied by epithelial thinning, inflammatory infiltration, disrupted tight-junction organization, reduced corneal nerve density, and decreased mechanical sensitivity. Nobiletin attenuated systemic metabolic abnormalities and partially restored corneal circadian organization by improving phase alignment and rhythmic gene network structure, while preserving epithelial barrier integrity and sensory innervation.

CONCLUSION

The cornea functions as a metabolically responsive peripheral circadian tissue. Nobiletin emerges as a potential therapeutic candidate to mitigate ocular surface pathology associated with metabolic stress.