Targeting the cGAS-STING Pathway: Modulating Inflammation, Oxidative Stress, and Autophagy for Novel Depression Therapies

Abstract: The pathological mechanisms underlying depression, a prevalent mental disorder, remain only partially elucidated despite extensive research efforts. Recent advancements have underscored the pivotal roles of multiple biological processes in the onset and progression of depression, including inflammation, oxidative stress, and autophagy. Inflammation is associated with the disruption of neurotransmitter systems and neural plasticity, whereas oxidative stress contributes to neuronal damage and impaired brain function. Moreover, moderate autophagy is essential for maintaining neuronal health. Dysregulation of autophagy may lead to the accumulation of damaged proteins and organelles, which can exacerbate depressive symptoms. Among the various molecular pathways involved, the cGAS-STING signalling pathway has emerged as a key regulator of these processes. Traditionally known for its role in detecting cytosolic DNA and initiating innate immune defences against pathogens, the cGAS-STING pathway has recently been implicated in regulating inflammatory responses, oxidative stress levels, and autophagy in the central nervous system. This dual function positions the cGAS-STING pathway as a potential link between immune dysregulation and the neurobiological foundations of depression. This paper offers a systematic overview of existing studies on the role of the cGAS-STING pathway in inflammation, oxidative stress, and autophagy within the central nervous system, particularly in the context of depression. The review reveals how modulation of the cGAS-STING pathway may influence these critical biological processes and thereby ameliorate depressive symptoms. Furthermore, the review discusses the therapeutic potential of targeting the cGAS-STING pathway and offers promising research directions. Ultimately, this paper aims to provide novel insights and approaches for developing more effective treatments for depression.