PPARs Mediated Diabetic Wound Healing Regulates Endothelial Cells Mitochondrial Function via Sonic Hedgehog Signaling

Background Diabetic foot ulcer (DFU) is a common and debilitating complication of diabetes, often leading to delayed wound healing. The peroxisome proliferator-activated receptors (PPARs) play a crucial role in regulating cellular metabolism and promoting angiogenesis. However, the mechanisms by which PPARs activation enhances wound healing, particularly in diabetic conditions, remain insufficiently understood. Methods Differentially expressed genes in DFU wounds and normal skin tissues were identified using the GEO database. PPARs expression in DFU neovascularization was validated by qRT-PCR, immunofluorescence, and western blotting. In vivo, diabetic mice treated with PPARs agonists (Chiglitazar) underwent wound healing assessment, including collagen deposition and angiogenesis. In vitro, high-glucose-induced endothelial cell models were used to evaluate PPARs activation effects on cell migration, tube formation, and mitochondrial function. Whole transcriptome sequencing and mitochondrial analysis were performed to explore the underlying mechanisms, particularly the sonic hedgehog (SHH) -mitochondrial axis. Results PPARs expression was significantly downregulated in DFU tissues (p < 0.05), and PPARs activation in diabetic mice enhanced wound healing, collagen deposition, granulation tissue proliferation, and angiogenesis (p < 0.05). In vitro, PPAR activation protected endothelial cells, promoting VEGF-A and CD31 expression, reducing apoptosis, and enhancing cell migration and tube formation (p < 0.05). Mechanistically, PPARs activated mitochondrial oxidative phosphorylation (OXPHOS) and membrane function through the SHH signaling pathway. SHH gene silencing reversed the effects of PPARs activation on mitochondrial function and angiogenesis. Conclusions PPARs signaling plays a critical role in DFU healing, with its inhibition linked to vascular dysfunction. Activation of the PPARs/SHH -mitochondrial axis significantly enhances endothelial cell metabolism and angiogenesis. This study provides insights into the molecular mechanisms of diabetic wound healing and supports the clinical potential of PPARs agonists for DFU treatment.