Metabolic reprogramming of macrophage-specific transketolase orchestrates angiogenesis in diabetic wounds

Abstract

Diabetic wound healing is profoundly impaired by macrophage metabolic dysfunction, which compromises angiogenesis. Here, we show a macrophage transketolase (TKT) as a crucial metabolic checkpoint governing vascular regeneration in diabetes. We demonstrate that loss of TKT in macrophages accelerates amino acid and fatty acid catabolism, elevates reactive oxygen species, and disrupts endothelial cell proliferation and differentiation. Mechanistically, hyperglycemia activates the AGEs-RAGE signaling cascade through suppressing TKT expression, establishing a pathological TKT-AGEs-RAGE axis that reprograms macrophage metabolism toward dysfunction. Then, we engineer a nanozyme-integrated hydrogel patch that selectively increases TKT level in macrophages, which rebalances macrophage metabolism, reduces oxidative stress, and rescues angiogenic capacity. In a diabetic pig model, localized delivery of the nano-system markedly accelerates wound closure and vascular repair. These findings not only elucidate a macrophage-specific TKT metabolic reprogramming mechanism for enhancing angiogenesis, but also offer a potential therapeutic strategy for the clinical management of diabetic wounds. Diabetes impairs wound healing by disrupting macrophage metabolism and angiogenesis. Here, authors identify macrophage-specific transketolase (TKT) as a metabolic checkpoint and develop a nanozyme hydrogel that restores macrophage TKT to promote vascular repair in diabetic wounds.