Preston McCourt ¹ Charles Day ¹ Souren Paul ^1,2*

• ¹ University of Minnesota Twin Cities, St. Paul, United States
• ² TERI School of Advanced Studies (TERI SAS), Vasant Kunj, National Capital Territory of Delhi, India

potentially contributing to abnormal autoimmune responses (1). Significant efforts are underway to discover specific and effective cGAS-STING inhibitors as researchers aim to blunt the cGAS-STING pathway in auto-immune disorders. A recent study showed that flavonoids are effective against the cGAS-STING pathway (6) and, in addition, flavonoids are known to have strong antiinflammatory activities (7). This research collection also highlights efficacy of Licorice extract and polysaccharide from Glycyrrhiza uralensis against cGAS-STING pathway (8,9).. Conversely, cGAS-STING agonists may offer therapeutic benefits; a recent study demonstrated that activating this pathway induces IFN-β and primes CD8+ T cells to target tumor cells, highlighting its potential in cancer immunotherapy (108). However, some research indicates that the cGAS-STING pathway may also facilitate tumorigenesis and metastasis (119).Chen et. al., offered a comprehensive review on the role of cGAS-STING in liver diseases such as viral hepatits B and hepatocellular carcinoma (12). During viral hepatitis, cGAS-STING signaling, and cytokine synthesis play a pivotal role in the antiviral-activity of hepatocytes. In hepatocellular carcinoma, the cGAS-STING pathway is activated by DNA damage, leading to IFN-1 release which in turn activates tumor-specific CD8 + T cell and helps induce systemic tumor immunity. Moreover, the authors suggest that the activation of the cGAS-IRF3 pathway is positively correlated with the severity of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD).Another comprehensive review article by Ramos et. al. discusses the role of cGAS in various gastrointestinal (GI) diseases including inflammatory bowel disease (IBD) and in GI malignancy (13). The authors explain the contribution of cGAS-mediated autophagy activation on intestinal epithelial cell integrity and innate immunity responses. Interestingly, cGAS shows a contradictory role in GI-related cancers, showing both oncogenic and anti-oncogenic functions.Formatted: Font color: Red Formatted: Font color: Red Ramos et al. also discuss non-canonical activation of cGAS in various GI-related diseases (13).STING-independent activation of cGAS includes an interaction between cGAS and Beclin-1, autophagy activation and degradation of pathogenic DNA. On another note, cGAS mediated autophagy of micronuclei shows an interaction between cGAS and essential autophagy protein LC3. DNA damage in the nucleus can also trigger nuclear translocation of cGAS which inhibits homologous recombination of double strand breaks by interacting with PARP-1. The authors also summarize the potential antagonists and agonists used against cGAS in various cell lines and mouse models (13).In another cGAS-STING review, Colangelo et. al. explain the importance of cGAS-STING signaling in radiation therapy (14). The review gives an overview of the cGAS-STING pathway in tumor microenvironment after ionizing radiation exposure. DNA damage (nuclear or mitochondrial) from ionizing radiation releases to cytosol within a short period of time and activates cGAS-STING (14). The authors discuss the importance of immune cells in terms of STING activation, whether activated directly or by tumor-derived cGAMP (14)