Single cell transcriptomic profiling of corneal epithelium of diabetic non-human primates reveals that FOXO3 regulates ROS by reprogramming glucose metabolism

Hyperglycemia leads to functional decline of various corneal cells, which induces corneal diseases. However, cellular and molecular mechanisms underlying how hyperglycemia affects the corneal epithelium have not been determined. Here, by undertaking single-cell transcriptomics of corneal epithelial cells obtained from healthy and diabetic non-human primates, we identified cell type-specific transcriptional alterations and shared changes across cell types, such as upregulation of FOXO3. Targeted depletion of FOXO3 in human corneal epithelial cells regulated metabolic remodeling by inhibiting glycolysis and oxidative phosphorylation. Furthermore, FOXO3 can not only sense reactive oxygen species (ROS) in corneal epithelial cells and scavenge ROS, but also mediate the proliferation and migration of corneal epithelial cells, demonstrating FOXO3 as a guardian factor in maintaining primate corneal epithelial homeostasis. Our study provides novel insight into the role of FOXO3 in metabolic remodeling and maintenance of ROS homeostasis in corneal epithelium at single-cell level, laying a foundation for decoding the molecular mechanism of the diagnosis and treatment of diabetic eye disease.