Role of cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway in diabetes and its complications

Diabetes mellitus(DM)is one of the major causes of mortality worldwide,with inflammation being an important factor in its onset and development.This review summarizes the specific mechanisms of the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING)pathway in mediating inflammatory responses.Furthermore,it compre-hensively presents related research progress and the subsequent involvement of this pathway in the pathogenesis of early-stage DM,diabetic gastroenteropathy,diabetic cardiomyopathy,non-alcoholic fatty liver disease,and other complic-ations.Additionally,the role of cGAS-STING in autonomic dysfunction and intes-tinal dysregulation,which can lead to digestive complications,has been discuss-ed.Altogether,this study provides a comprehensive analysis of the research advances regarding the cGAS-STING pathway-targeted therapeutic agents and the prospects for their application in the precision treatment of DM.

New Frontiers on Intracellular cGAS Activation:Molecular Mechanisms,Cellular Signaling,and Therapeutic Strategies

Cyclic GMP-AMP(cGAMP)synthase(cGAS)plays a pivotal role in the innate immune system.As the primary DNA sensor in cells,cGAS binds to dsDNA in the cytoplasm and forms cGAS-DNA liquid-liquid phase separation(LLPS)and activates its catalytic activity.This activation triggers the cGAS-stimulator of interferon genes(STING)signaling pathway,establishing an efficient system for pathogen detection.Beyond pathogen surveillance,cGAS performs a diverse range of roles,involved in inflammatory response,metabolic homeostasis,DNA damage repair,and cell death.These biological functions regulate cellular physiological homeostasis and influence the occurrence and development of diseases.This review provides an overview of the structure,localization,and intracellular biological functions of the cGAS-STING signaling pathway and cGAS-DNA LLPS.Furthermore,we discuss their contribution to the development of tumors,autoimmune diseases,and inflammatory diseases and highlight the innovative strategies in modulating cGAS activity,either through activation or inhibition,as a promising therapeutic approach.

The multifaceted functions of cGAS

Pattern recognition receptors arecritical forthe sensing of pathogen-associated molecular patterns or danger-associated molecular patterns and subsequent mounting of innate immunityandshaping ofadaptive immunity.The identification of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)synthase(cGAS)as a major cytosolic DNA receptor is a milestone in the field of DNA sensing.The engagement of cGAS by double-stranded DNA from different origins,including invading pathogens,damaged mitochondria,ruptured micronuclei,and genomic DNA results in the generation of cGAMP and activation of stimulator of interferon genes,which thereby activates innate immunity mainly characterized by the activation of type I interferon response.In recent years,great progress has been made in understanding the subcellular localization and novel functions of cGAS.In this review,we particularlyfocus on summarizingthe multifaceted roles ofcGAS in regulating senescence,autophagy,cell stemness,apoptosis,angiogenesis,cell proliferation,antitumor effect,DNA replication,DNA damage repair,micronucleophagy,as well as cell metabolism.