Nuclear Receptor Subfamily 1 Group D Member 1 Promotes Wound Healing in Diabetic Mice through Transcriptional Repression of Stimulator of Interferon Genes.

Diabetic foot ulcer is one of the most debilitating complications of diabetes mellitus, primarily driven by persistent inflammation and impaired angiogenesis. This study investigates the role of the circadian clock protein, nuclear receptor subfamily 1 group D member 1 (NR1D1), in diabetic wound healing and elucidates its underlying mechanism. Clinical and experimental analyses revealed that NR1D1 levels were significantly reduced in both the serum and cutaneous wounds of diabetic patients and mice, with down-regulated NR1D1 correlating with delayed wound closure. Functionally, NR1D1 knockout markedly exacerbated wound healing impairment in diabetic mice, accompanied by elevated proinflammatory cytokines and dysfunctional angiogenesis. Conversely, NR1D1 overexpression suppressed IL-6 and IL-1β expression and rescued high-glucose-induced vascularization deficits in vitro. Additionally, diminished NR1D1 expression coincided with hyperactivated stimulator of interferon genes (STING) signaling in both diabetic skin wounds and high-glucose-treated human umbilical vein endothelial cells. Luciferase assays confirmed that NR1D1 directly represses human STING promoter activity. Taken together, the results indicated that NR1D1 deficiency severely deteriorates wound healing by provoking inflammation and dysregulating endothelial angiogenesis, which is driven by the high-glucose-triggered derepression of NR1D1-mediated transcriptional silencing of STING.