Quercetin attenuates neutrophil extracellular trap formation in uveitis through orchestrating the cGAS–STING signaling pathway

Abstract

Uveitis is an autoimmune disease with a high rate of blindness. Clinically, treatments of uveitis mainly rely on corticosteroids and immunosuppressants, which are prone to recurrence and carry significant side effects. Quercetin, a natural flavonoid compound, exhibits anti-inflammatory, antioxidant, and immunomodulatory effects. However, its potential role in uveitis through regulating neutrophil extracellular traps (NETs) by modulating the cGAS–STING pathway remains unclear. This study investigated the therapeutic effects and mechanisms of quercetin in uveitis by establishing an experimental autoimmune uveitis (EAU) rat model and analyzing peripheral blood samples from uveitis patients. The results showed that quercetin significantly reduced ocular inflammation and retinal structural damage in EAU rats, lowered histopathological scores, and decreased blood flow density. Mechanistically, quercetin improves mitochondrial dysfunction, inhibits cGAS–STING pathway activation, and reduces NF-κB phosphorylation and pro-inflammatory factor release, ultimately suppressing NET marker expression and formation. Molecular docking revealed strong binding affinities between quercetin and cGAS, STING, and MPO. Furthermore, the STING inhibitor H151 exhibited similar effects to quercetin, further confirming the pivotal role of the cGAS–STING pathway in NET formation. Collectively, this study first elucidates the regulatory role of quercetin in modulating the cGAS–STING pathway to inhibit NET release, thereby alleviating the degree of inflammation in uveitis. This study provides experimental evidence and theoretical support for quercetin as a potential anti-uveitis therapeutic agent.