Kurarinone Alleviates cGAS-STING-Triggered Inflammatory Diseases by Targeting STING

Aberrant activation of the cGAS-STING pathway has been implicated in the pathogenesis of diverse inflammatory diseases. Kurarinone, a flavonoid compound isolated from Sophorae tonkinensis Radix et Rhizoma, has been reported to exhibit anti-inflammatory effects and is used to treat inflammatory diseases. But the effect of kurarinone on the cGAS-STING pathway has not been well studied. We aimed to investigate the impact of Kurarinone on cGAS-STING pathway activation and its protective effect against cGAS-STING-mediated inflammatory diseases. BMDMs and THP-1 cells pretreated with Kurarinone or vehicle were stimulated with ISD or various STING agonists; the protein level of p-IRF3 was analyzed by western blotting, and the secretion and mRNA level of inflammatory cytokines were detected by ELISA and qPCR, respectively. To further explore the potential targets and molecular mechanisms of Kurarinone, nucleocytoplasmic separation assays, STING oligomerization experiments, cellular thermal shift assays, drug affinity responsive target stability assays, and molecular docking were conducted. Additionally, DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models were used to evaluate the effects of Kurarinone on cGAS-STING-mediated inflammatory diseases. In vitro, Kurarinone inhibited the phosphorylation of STING and IRF3, reduced IFNβ release, and downregulated the transcription of IFNβ, IL-1β, CXCL10, IL-6, TNF-α, and ISG15, in ISD-stimulated BMDMs and THP-1 cells. Additionally, Kurarinone suppressed IRF3 nuclear translocation, disrupted the interaction between STING and IRF3, but did not affect STING oligomerization. Furthermore, Kurarinone reduced the thermostability of STING while increasing its susceptibility to proteolytic degradation. The molecular docking results indicated a strong interaction between Kurarinone and STING. In vivo, Kurarinone attenuated the inflammatory response in DSS-induced inflammatory bowel disease and ConA-induced autoimmune hepatitis models by inhibiting cGAS-STING signaling activation. In conclusion, Kurarinone targets the STING protein to interfere with the interaction between IRF3 and STING, thereby inhibiting the activation of the cGAS-STING signaling pathway. Additionally, Kurarinone ameliorates inflammatory diseases by suppressing the cGAS-STING pathway. This study provides a potential candidate drug for the clinical treatment of STING-driven inflammatory diseases.