Glycyrrhetinic acid blocks SARS‐CoV‐2 infection by activating the cGAS‐STING signalling pathway

Background and Purpose Traditional Chinese medicine (TCM) played an important role in controlling the COVID‐19 pandemic, but the scientific basis and its active ingredients are still weakly studied. This study aims to decipher the underlying anti‐SARS‐CoV‐2 mechanisms of glycyrrhetinic acid (GA). Experimental Approach GA's anti‐SARS‐CoV‐2 effect was verified both in vitro and in vivo. Homogeneous time‐resolved fluorescence assays, biolayer interferometry technology, and molecular docking were employed to examine interactions of GA with human stimulator of interferon genes (hSTING). Immunofluorescence staining, western blot, and RT‐qPCR were used to investigate nuclear translocation of interferon regulatory factor 3 (IRF3) and levels of STING target genes. Pharmacokinetics of GA was studied in mice. Key Results GA could directly bind to Ser162 and Tyr240 residues of hSTING, thus up‐regulating downstream targets and activation of the STING signalling pathway. Such activation is crucial for limiting the replication of SARS‐CoV‐2 Omicron in Calu‐3 cells and protecting against lung injury induced by SARS‐CoV‐2 Omicron infection in K18‐ACE2 transgenic mice. Immunofluorescence staining and western blot indicated that GA increased levels of phosphorylated STING, phosphorylated TANK‐binding kinase‐1, and cyclic GMP‐AMP synthase (cGAS). Importantly, GA increased nuclear translocation of IRF3. Pharmacokinetic analysis of GA in mice indicated it can be absorbed into circulation and detected in the lung at a stable level. Conclusion and Implications Activation of the cGAS‐STING pathway through the GA‐STING‐IRF3 axis is essential for the antiviral activity of GA in mice, providing new insights into the potential translation of GA for treating SARS‐CoV‐2 in patients.