Exosomal FASN Impairs Diabetic Wound Angiogenesis Via Mitochondrial Dysfunction

To delineate how Fasn-enriched circulating exosomes in diabetes disrupt endothelial lipid homeostasis and angiogenesis via mitochondrial regulation in the wound healing process. Serum exosomes from type 2 diabetic mice and controls (n=10) were characterized by proteomics and lipidomics. Fasn-silenced exosomes were generated via AAV-edited donor mice (n=6) for diabetic wound models. Human umbilical vein endothelial cells (HUVECs) were treated with circulating exosomes, followed by lipidomics, RNA-seq, Seahorse mitochondrial assays and angiogenic detection. Molecular mechanisms (DRP1-Ser616 phosphorylation, mTOR-mitophagy axis, cGAS-STING, SASP factors) were analyzed through RNA-seq, immunoblotting, and pharmacological interventions. Diabetic exosomes exhibited 3.2-fold higher Fasn than controls. Fasn transfer triggered lipid overload and oxidative stress in HUVECs, driving mitochondrial fission via Drp1-Ser616 phosphorylation. Lipid accumulation activated mTOR-dependent mitophagy inhibition, further resulting in excessive damaged mitochondria and mtDNA leakage. Cytosolic mtDNA activated cGAS-STING and upregulated SASP factors, impairing tube formation by 38%. Fasn silencing in diabetic mice restored angiogenesis (2.16-fold CD31+ vessels) and accelerated wound closure by 10.5% at D10 (P<0.01). Fasn-enriched circulating exosomes in diabetes drive diabetic angiogenesis impairment through lipid metabolism disturbance-induced mitochondrial fragmentation and SASP phenotype in endothelial cells. Targeting exosomal Fasn or quality control represents a translatable strategy for diabetic wound healing.