Luteolin ameliorates diabetic retinopathy through activation of the Nrf2/Keap1 and SIRT3/AMPK antioxidant axes and suppression of cGAS-STING and Wnt/β-catenin pathways in experimental rats.

Abstract

Diabetic retinopathy (DR) is a sight-threatening complication of diabetes, which involves metabolic dysfunction, oxidative stress, inflammation, and angiogenesis. Luteolin, a dietary flavonoid, was examined for pleiotropic protective effects in streptozotocin-induced diabetic rats. Adult male Sprague-Dawley rats were assigned to five groups (n = 6): Control, Diabetic, Diabetic + Luteolin 50 mg kg⁻¹, Diabetic + Luteolin 100 mg kg⁻¹, and Diabetic + Metformin (300 mg kg⁻¹); treatments were given orally for eight weeks. Luteolin normalized fasting blood glucose (reduced by 48% at 100 mg/kg), restored circulating insulin (increased by 56.5%), reduced polyphagia (normalized to control levels), and prevented weight loss (maintaining 85% of initial body weight), indicating the recovery of systemic metabolism. Histology confirmed preservation of the total, inner, and outer retinal thickness, and a marked reduction in vascular leakage. Biochemically, luteolin lowered malondialdehyde, protein carbonyls, and advanced glycation end-products while elevating superoxide dismutase, catalase, and glutathione peroxidase, thus re-establishing the redox balance. Gene and protein analyses revealed synchronous pathway modulation: activation of the Nrf2/Keap1 antioxidant axis; upregulation of the mitochondrial SIRT3-AMPK-FOXO3 network and quality-control genes (Pink1, Park2, Sod2, Gpx4, and Hspa1a), suppression of the cGAS-STING-TBK1 innate immune cascade and downstream NF-κB-driven cytokines (Tnf, Il1b, Il6, Ifnb1); and inhibition of canonical Wnt/β-catenin signaling with reciprocal restoration of Gsk3b and downregulation of Vegfa. In conclusion, luteolin exerts comprehensive protective effects against DR by simultaneously correcting metabolic, oxidative, inflammatory, and angiogenic imbalances in diabetic rats. These findings highlight luteolin’s potential as an orally available and safe candidate for the prevention or delay of diabetic retinopathy progression.