Luteolin Alleviates Diabetic Foot Ulcers Through Improving KDM4C/ITGA1‐mediated Functional Impairments of AGEs‐Induced Senescent Endothelial Cell

Endothelial dysfunction driven by senescent endothelial cells represents a pivotal mechanism underlying delayed wound healing in diabetic foot ulcers (DFU). Luteolin can enhance the angiogenesis of diabetic wounds, and improve cellular senescence. This study investigated its mechanism in DFU using advanced glycosylation end products (AGEs)-treated HUVECs and streptozotocin (STZ) -induced diabetic rats with surgical wounds. Integrin α1 (ITGA1) was upregulated in wound tissues of diabetic patients and AGEs-induced HUVECs. ITGA1 knockdown improved functional impairments and senescence in AGEs-treated HUVECs, as demonstrated by the elevated abilities of proliferation, migration and tube-formation, the decreased SA-β-galactosidase positive cells, and the reduced expression of senescence markers (P16, P21 and P53), where CCK-8, EdU, Transwell, and tube formation, and SA-β-galactosidase staining assay and Western blot were utilized. Luteolin significantly improved AGEs-induced senescence and functional impairments of HUVECs, and accelerated wound healing in diabetic rats. Conversely, overexpression of ITGA1 abrogated these protective effects. Mechanistic studies revealed that Luteolin suppressed ITGA1 transcription by inhibiting lysine-specific demethylase 4 C (KDM4C)-mediated demethylation of H3K9me3 at the ITGA1 promoter. Additionally, the epidermal growth factor receptor (EGFR)/MEK/ERK pathway was involved in Luteolin's therapeutic effects on DFU wound healing. In conclusion, Luteolin alleviated DFU through improving KDM4C/ITGA1-mediated functional impairments in AGEs-induced senescent endothelial cell via the EGFR/MEK/ERK pathway, providing novel insights into the molecular mechanisms underlying Luteolin's therapeutic potential for DFU.