Integrated bioinformatics and experimental validation identifies SOX2 as a key therapeutic target for chronic atrophic gastritis/gastric cancer-depression comorbidity

Vollständiger Abstract

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Objective Gastric cancer (GC) and its precursor chronic atrophic gastritis (CAG) exhibit a high comorbidity with depression. However, the core molecular mechanisms underlying stomach-brain axis-mediated crosstalk between GC/CAG and depression remain poorly clarified. This study attempted to screen pivotal molecules correlated with the bidirectional correlation between GC/CAG and depression, and explore the inflammatory regulatory network through integrated bioinformatics analysis and systematic in vivo and in vitro validation, so as to provide potential clues for revealing their interactive relationship. Methods We integrated transcriptomic datasets of CAG, GC, and depression to identify shared differentially expressed genes, further prioritized core diagnostic genes by machine learning, and characterized their biological functions through functional enrichment analysis. In vivo validation was performed in MNNG-induced CAG/GC rat models, including behavioral tests, histopathological evaluation, and gene expression analysis of gastric and brain tissues. Molecular docking and molecular dynamics simulations were performed to assess the binding affinity and structural stability between MNNG and SOX2. In vitro experiments explored how SOX2 expression levels correlate with NOTCH signaling/IL-6 in gastric epithelial cells and paracrine effects on neuronal inflammation. Results A total of 21 overlapping differentially expressed genes were screened out, among which 8 core diagnostic genes with AUC values greater than 0.7 were identified, and SOX2 presented the highest diagnostic efficiency with an AUC of 0.849. The MNNG-induced model rats displayed reduced activity and anhedonia-like behavior, accompanied by decreased SOX2 expression and activated NOTCH/IL-6 signaling in gastric and brain tissues. Molecular docking results confirmed that the binding energy between MNNG and SOX2 was −5.5 kcal/mol. In vitro cellular assays revealed an association between SOX2 downregulation and NOTCH cascade activation alongside elevated IL-6 secretion; neuronal cells cultured with gastric cancer cell-derived conditioned medium exhibited concurrent IL-6-related inflammatory alterations. Conclusion This study characterizes the bidirectional correlative relationship between GC/CAG and depression mediated by the stomach-brain axis. SOX2 is characterized as a key molecule correlated with the regulation of the NOTCH/IL-6 signaling pathway in this interactive network, indicating its potential as a diagnostic biomarker and therapeutic target for GC/CAG complicated with depression.