Alpha-ketoglutarate restores oral epithelial homeostasis via FOXM1-mediated cell cycle regulation.

The rapid repair of intraoral mucosal injuries is crucial for restoring oral epithelial homeostasis. Alpha-ketoglutarate (αKG), a multi-potential metabolite involved in protein synthesis, epigenetic regulation, and immune response, holds the potential in tissue homeostasis and wound repair. Here, we report that administration of αKG accelerates palatal wound healing, with enhanced re-epithelialization and increased collagen deposition. αKG increases the number of Ki67+ cells in the palatal epithelium and elevates the percentage of EdU+ cells in cultured human gingival epithelial cells (HGEs). Importantly, αKG treatment upregulates cell cycle-related pathways, primarily modulating the activity of CDK1-cyclin A and CDK1-cyclin B complexes. Mechanistically, αKG promotes the expression of FOXM1 and mediates the downstream cell cycle regulation. To further optimize local delivery of αKG, we develop the polyethyleneimine (PEI)/polyacrylic acid (PAA)/αKG supramolecular network to promote oral wound healing. Taken together, our findings demonstrate that αKG restores oral epithelial homeostasis via FOXM1-mediated cell cycle regulation, highlighting its therapeutic potential for oral wound repair.