Calcium oxalate (CaOx) kidney stone disease is common and highly recurrent, but the upstream mechanisms that predispose renal tubules to crystal deposition remain unclear. This study investigated whether disruption of environmental light-dark cycles promotes CaOx crystal deposition through NR1D1-dependent metabolic and redox regulation. Mouse models of light-cycle disruption were established with or without glyoxylate-induced hyperoxaluria, and NR1D1-deficient mice were used for in vivo validation. Oxalate-injured HK-2 cells were used for pharmacological and genetic experiments. Transcriptomics, histology, biochemical assays, ROS and mitochondrial membrane potential analyses, crystal adhesion assays, ChIP-qPCR, and dual-luciferase reporter assays were performed. Disrupted lighting conditions promoted renal CaOx crystal deposition and further exacerbated glyoxylate-induced crystal accumulation, accompanied by tubular injury, oxidative stress, reduced antioxidant capacity, and altered circulating insulin and melatonin levels. NR1D1 expression was suppressed, whereas IRS1 signaling and crystal adhesion-related proteins were increased. SR9009 treatment and NR1D1 overexpression alleviated oxalate-induced mitochondrial dysfunction, ROS accumulation, and crystal adhesion, whereas NR1D1 deficiency aggravated renal injury in vivo. Mechanistically, NR1D1 directly bound the IRS1 promoter and repressed IRS1 transcription, thereby preserving FOXO1/GPX4-mediated antioxidant defense. These findings identify an NR1D1-IRS1-FOXO1/GPX4 axis linking light-cycle disruption and circadian-associated dysregulation to oxidative tubular injury and CaOx crystal deposition.
Circadian Biology