Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, but currently, no pharmacological NLRP3 inhibitor has been approved. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and dextran sodium sulfate–induced (DSS-induced) colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH). Collectively, our study identifies echinatin as a potentially novel inhibitor of NLRP3 inflammasome, and its use may be developed as a therapeutic approach for the treatment of NLRP3-driven diseases.

Background: Inflammation and fibrosis are typical symptoms of non-alcoholic steatohepatitis (NASH), which is one of the most common chronic liver diseases. The cGAS-STING signaling pathway has been implicated in the progression of NASH, and targeting this pathway may represent a new therapeutic strategy. Licorice is a widely used herb with anti-inflammatory and liver-protective properties. In this study, we assessed the effect of licorice extract on the cGAS-STING pathway.Methods: Bone marrow-derived macrophages (BMDMs) were treated with licorice extract and then stimulated with HT-DNA, 2'3'-cGAMP, or other agonists to activate the cGAS-STING pathway. Quantitative real-time PCR and western blot were conducted to analyze whether licorice extract could affect the cGAS-STING pathway. Methionine and choline-deficient diet (MCD) was used to induce NASH in mice, which were treated with licorice extract (500 mg/kg) by gavage and/or c-176 (15 mg/kg) by intraperitoneal injection every 2 days. After 6 weeks of treatment, histological analysis of liver tissue was performed, along with measurements of plasma biochemical parameters.Results: Licorice extract inhibits cGAS-STING pathway activation. Mechanistically, it might function by inhibiting the oligomerization of STING. Treatment with licorice extract reduced inflammation and fibrosis in MCD diet-induced NASH mice models. Furthermore, we found that the therapeutic effect of combination treatment with licorice extract and C-176 (STING inhibitor) on the pathology and fibrosis of MCD diet-induced NASH models was similar to that of licorice extract or C-176 administered alone.Conclusion: Licorice extract can inhibit the cGAS-STING pathway and improve hepatic inflammation and fibrosis in NASH mice models. It strongly suggests that licorice extract may be a candidate therapeutic for NASH.

Hepatic fibrosis is the final pathway of several chronic liver diseases, which is characterized by the accumulation of extracellular matrix due to chronic hepatocyte damage. Activation of hepatic stellate cells and oxidative stress (OS) play an important role in mediating liver damage and initiating hepatic fibrosis. Hence, hepatic fibrosis can be reversed by inhibiting multiple channels such as oxidative stress, liver cell damage, or activation of hepatic stellate cells. Liuwei Wuling Tablets is a traditional Chinese medicine formula with the effect of anti- hepatic fibrosis, but the composition and mechanism of reversing hepatic fibrosis are still unclear. Our study demonstrated that one of the main active components of the Chinese medicine Schisandra chinensis, schisandrin C (Sin C), significantly inhibited oxidative stress and prevented hepatocyte injury. Meanwhile one of the main active components of the Chinese medicine Curdione inhibited hepatic stellate cell activation by targeting the TGF-β1/Smads signaling pathway. The further in vivo experiments showed that Sin C, Curdione and the combination of both have the effect of reversing liver fibrosis in mice, and the combined effect of inhibiting hepatic fibrosis is superior to treatment with Sin C or Curdione alone. Our study provides a potential candidate for multi-molecular or multi-pathway combination therapies for the treatment of hepatic fibrosis and demonstrates that combined pharmacotherapy holds great promise in the prevention and treatment of hepatic fibrosis.