Macrophage-derived IL-1β directs fibroblast progenitor cell fate via metabolic reprogramming in wound healing.

The oral mucosa exhibits unique regenerative properties and distinct wound healing dynamics compared to facial skin, providing a valuable model for studying tissue-specific repair mechanisms. Using a rigorously controlled mouse model combined with single-cell transcriptomics, we identified a novel mechanism underlying this tissue-specific difference. Our study revealed a population of fibroblast progenitors in the oral buccal mucosa that rapidly activate and differentiate into mature fibroblasts, contributing to effective wound resolution. Mechanistically, IL-1β derived from tissue-resident macrophages activates NFκB signals in these progenitors, inducing a metabolic shift from glycolysis to oxidative phosphorylation in a proteasome-dependent manner. This metabolic reprogramming supports stem cell differentiation and contributes to the unique regenerative pattern of the oral buccal mucosa. Our findings highlight the specialized healing mechanisms of the oral tissue and suggest that modulating proteasome activation and the IL-1β/NFκB axis may offer new therapeutic avenues for enhancing wound repair in tissue requiring extensive connective remodeling, such as skin or gingiva.