SR‐717, a Non‐Nucleotide STING Agonist, Displayed Anti‐Radiation Activity in a IL‐6 Dependent Manner

ABSTRACT Ionizing radiation (IR) induced damages are common complications of radiotherapy for tumors, severely limiting the intensity and therapeutic efficacy of the radiotherapy program. Emerging data indicated that the cGAS‐STING pathway has paradoxical effects on IR‐induced damage. SR‐717, as a non‐nucleotide, small‐molecule stimulator of interferon genes (STING) agonist, has been proven that it could activate the STING signaling pathway. In this work, we try to explore the radioprotection of the STING signaling pathway and figure out whether SR‐717 could be a potential intestinal radioprotective agent. C57BL/6 mice were intraperitoneally treated with SR‐717 or normal saline (NS). By analyzing the survival rate, body weight, and the number of peripheral blood cells after IR exposure, we found that SR‐717 improved the survival rate and body weight of mice, protected the intestine from IR‐induced damage as well as hematopoietic damage, and promoted the regeneration of intestinal stem cells (ISCs). Cell viability and apoptosis after irradiation were detected after stimulation of MODE‐K cells with SR‐717 or PBS. We found that SR‐717 increased cell viability and inhibited apoptosis in vitro. The mechanism of SR‐717 in intestinal radiation protection was investigated by RNA‐seq. The results of RNA‐seq and qRT‐PCR suggested that SR‐717 significantly activated the immune system via the STING‐IL‐6 signaling pathway. In addition, we discussed the role of TLR2 in SR‐717‐mediated anti‐radiation activity, and TLR2 deletion significantly reversed the radioprotective effects of SR717. In conclusion, we proved STING signaling activation displayed anti‐radiation activity and found SR‐717 displayed anti‐radiation activity via the STING‐IL‐6 signaling pathway, suggesting SR‐717 could be a potential intestinal radioprotective agent.