Abstract:Wound healing is a spatiotemporally orchestrated biological process involving inflammatory regulation，proliferative repair，and tissue remodeling. Its core lies in the dynamic interplay between collective cell migration and metabolic networks. Re-epithelialization，the pivotal phase of wound closure，relies on collective migration of epithelial cells driven by functionally specialized leader cells. This review systematically elucidates the molecular mechanisms underlying the synergistic regulation of leader cell function formation by lipid metabolism and mechanical signaling：cholesterol- enriched lipid rafts enhance mechano transduction via integrin-focal adhesion kinase signaling，while polyunsaturated fatty acid metabolism promotes pseudopod extension through actin nucleation complex activation，establishing spatially complementary regulatory networks. Mechanical sensing triggers mitochondrial metabolic reprogramming via calcium signaling，significantly enhancing energy supply efficiency to support cellular motility. Lipid metabolites translate mechanical stimuli into stable migratory phenotypes through epigenetic modifications，enabling persistent regulation of cellular behavior. In pathological microenvironments such as diabetic wounds，where lipid metabolic homeostasis is disrupted，intervention strategies targeting the metabolism-mechanics coupling network can rejuvenate reparative cell functions，offering novel therapeutic avenues for chronic wounds. This review elucidates the multidimensional regulatory roles of metabolic reprogramming in tissue repair and establishes a theoretical foundation for developing regenerative medicine strategies based on precise modulation of the metabolic microenvironment.