Over-activation of STING Induces Endoplasmic Reticulum Stress and Apoptosis via Binding Affinity with IP3R in Salivary Gland Cells of Sjögren's Syndrome

Background Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and cell death of salivary gland epithelial cells (SGECs). However, the connection between immune signaling to the fate of SS remains unclear. Methods We demonstrated that high lactate levels induces the cGAS-STING singaling transduction in SGECs of SS patients. Furthermore, in vitro study in salivary gland A253 cell line and in vivo study of NOD/Ltj mice model show that lactate-induced abnormal activation of STING results in endoplasmic reticulum (ER) stress. Results Mechanistically, we found that overactivated STING disrupts Ca ²⁺ homeostasis in ER by altering its interaction with the inositol trisphosphate receptor (IP3R), consequently causing ER damage, triggering ER stress and cell apoptosis. Conclusion This research sheds new light on the mechanism of SS but also reveals the pivotal roles of STING-IP3R binding, providing novel avenues for the treatment of autoimmune disorders.