Abstract

Background Persistent inflammation-driven impaired angiogenesis is a key factor in the chronicity of diabetic ulcers (DU). The flavonoid breviscapine is clinically used in China for DU, but its precise role and underlying mechanisms remain unclear. Purpose To investigate the therapeutic effects and mechanistic basis of breviscapine in DU wound healing. Methods A DU mice model was established to evaluate the efficacy of Bre. The potential mechanism of breviscapine in DU treatment was investigated by examining mice wound skin using proteomics techniques. A glucose-induced RAW264.7 cells and human umbilical vein endothelial cells (HUVECs) conditioned medium model was employed to validate the mechanism with molecular biological techniques. Results Breviscapine alleviated pathological skin damage, promoted collagen deposition, and enhanced wound angiogenesis in DU mice. Breviscapine significantly facilitated macrophage toward the reparative M2 phenotype, suppressed pro-inflammatory cytokines IL-1β and TNF-α, and increased the secretion of anti-inflammatory IL-10 and pro-angiogenic VEGF in both DU mice and glucose-induced RAW264.7 cells. Macrophages exposed to hyperglycemia inhibited HUVECs proliferation, migration, and tubule formation, whereas breviscapine reversed these impairments. Unbiased proteomic and cellular energy metabolism analysis further revealed that mitochondrial enzyme arginase-2 (Arg2) serves as a key molecular switch driving macrophage metabolic reprogramming and polarization imbalance in DU. Arg2 overexpression exacerbated mitochondrial dysfunction in macrophages and drived glycolytic metabolism by activating the downstream HIF-1α pathway, suppressing M2 polarization. Simultaneously, Arg2-overexpressing macrophages further exacerbated the impaired angiogenesis of HUVECs, whereas Arg2 silencing reversed these alterations. Moreover, breviscapine counteract