From mitochondrial oxidative stress to neuroinflammation: integrated proteomic and transcriptomic profiling reveals the role of the ROS/TXNIP/NLRP3 signaling pathway in anxious depression

BackgroundAnxious depression is a prevalent affective disorder characterized by typical depressive symptoms accompanied by persistent anxiety. Increasing evidence suggests that mitochondrial oxidative stress and neuroinflammation contribute to its onset and progression; however, the precise mechanisms linking these processes remain elusive.MethodsA rat model of anxious depression was established via chronic restraint stress combined with corticosterone administration.

Integrated proteomic and transcriptomic analyses were performed to profile differentially expressed molecules in the hippocampus, with key signaling pathways validated by Western blot and qPCR. A Mito-TEMPO intervention group was introduced to evaluate the role of mitochondrial oxidative stress, involving behavioral tests, mitochondrial ultrastructure and reactive oxygen species (ROS) detection, and analysis of autophagy-, inflammation-, and apoptosis-related markers.

Additionally, in vitro experiments were conducted using TXNIP siRNA knockdown in BV2 microglia to further verify the role of TXNIP.ResultsProteomic and transcriptomic profiling identified dysregulation of inflammatory-, synaptic-, and mitophagy-related pathways in the hippocampus of model rats, with prominent upregulation of TXNIP and activation of the NLRP3 inflammasome. Model rats exhibited excessive mitochondrial ROS (mtROS) accumulation, suppressed PINK1/Parkin-mediated mitophagy, neuronal injury, and anxiety- and depression-like behaviors.