CircGDI2 promotes the healing of diabetic wounds by mediating macrophage polarization through the SIRT2/TFAM axis.

Chronic non-healing diabetic wounds are a severe complication of diabetes, associated with markedly elevated rates of disability and lower limb amputation, and remain a major clinical therapeutic challenge due to their persistent pathological microenvironment. Alleviating the excessive chronic inflammatory response in diabetic wounds is a pivotal strategy to restore normal tissue repair and promote wound healing. In this study, we found that exosomes derived from hair follicle dermal stem cells (HFDSC-Exos) significantly increased the proportion of anti-inflammatory M2-polarized macrophages and effectively accelerated diabetic wound closure under high-glucose (HG) conditions. Through whole-transcriptome sequencing and functional validation, we identified hsa_circ_0005379 (CircGDI2) as a key functional circRNA cargo in HFDSC-Exos. Mechanistically, CircGDI2 directly binds to silent information regulator 2 (SIRT2), a NAD⁺-dependent deacetylase, and upregulates the expression of mitochondrial transcription factor A (TFAM), thereby modulating macrophage polarization toward the M2 phenotype. This regulatory axis robustly reduces the production of reactive oxygen species (ROS) and advanced glycation end-products (AGEs), suppresses the secretion of proinflammatory cytokines, ameliorates the pathological inflammatory microenvironment of diabetic wounds, and ultimately promotes efficient wound healing. These findings demonstrate that CircGDI2 serves as a key functional circRNA cargo in HFDSC-Exos, mediating macrophage polarization via the SIRT2/TFAM axis and provide a promising exosome-based targeted therapeutic strategy for the clinical management of chronic diabetic wounds.