Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway

Abstract Random-pattern skin flaps are widely employed in tissue reconstruction, however, their survival is frequently hindered by ischemia, leading to necrosis. Metabolic alterations have been implicated in playing critical roles in angiogenesis during tissue repair. Using RNA sequencing analysis in a mouse model, we identified significant disruptions in glutamine metabolism, which substantially impaired angiogenesis within random-pattern skin flaps. Although local glutamine repletion failed to alleviate ischemia, administering α-ketoglutarate (α-KG) markedly promoted angiogenesis, as evidenced at both gene and protein levels. In human umbilical vein endothelial cells,α-KG enhanced the stability of hypoxia-inducible factor (HIF-1) alpha through activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Notably, α-KG treatment improved flap viability by augmenting blood perfusion, an effect correlated with upregulation of vascular endothelial growth factor expression. Together, these results reveal a novel mechanism by which α-KG enhances random-pattern skin flap viability via promoting angiogenesis through the PI3K/Akt/HIF-1α pathway, offering promising therapeutic insights for improving flap survival.