The microbiota-gut-brain axis is involved in the pathogenesis of depression; however, whether the cGAS-STING signaling pathway contributes to onset and progression of depression via gut microbiota dysbiosis remains unknown. This study aims to investigate the role of the cGAS-STING signaling pathway in chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors. Additionally, it aimed to identify novel downstream signaling factors of this pathway. A comprehensive mechanistic investigation was conducted using CUMS rats, HT22 cells, and cGAS+/- mice, with behavioral tests to assess depressive-like behaviors. Changes in the gut-brain axis and the underlying molecular mechanisms were systematically evaluated by histopathological staining, transmission electron microscopy, immunohistochemistry, immunofluorescence, Western blotting, co-immunoprecipitation (Co-IP), transcriptomics, metabolomics, and 16S rRNA sequencing. The results showed that in rats, CUMS induced hippocampal and intestinal damage, inflammation, cGAS-STING activation, and SATB2 upregulation, accompanied by intestinal tight junction impairment. Co-IP assays suggested an interaction between SATB2 and STING/IRF3. Additionally, CUMS rats exhibited altered gut microbiota (decreased beneficial genera, increased opportunistic pathogens) and elevated tobramycin, acarbose, and inosine levels. SATB2 was identified as a potential novel downstream molecule of the cGAS-STING axis, potentially associated with depressive-like behaviors via CUMS-induced gut-brain axis dysregulation. This finding provides a basis for antidepressant intervention strategies targeting this pathway.
