Background:Type 2 diabetes-associated cognitive dysfunction (DCD) is a chronic
complication of diabetes that has gained international attention. The medicinal compound Banxia
Xiexin Decoction (BXXXD) from traditional Chinese medicine (TCM) has shown potential in
improving insulin resistance, regulating endoplasmic reticulum stress (ERS), and inhibiting cell
apoptosis through various pathways. However, the specific mechanism of action and medical value
of BXXXD remain unclear.Methods:We utilized TCMSP databases to screen the chemical constituents of BXXXD and
identified DCD disease targets through relevant databases. By using Stitch and String databases,
we imported the data into Cytoscape 3.8.0 software to construct a protein-protein interaction (PPI)
network and subsequently identified core targets through network topology analysis. The core
targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of
Genes and Genomes (KEGG) pathway analyses. The results were further validated through in
vitro experiments.Results:Network pharmacology analysis revealed the screening of 1490 DCD-related targets and
190 agents present in BXXXD. The topological analysis and enrichment analysis conducted using
Cytoscape software identified 34 core targets. Additionally, GO and KEGG pathway analyses
yielded 104 biological targets and 97 pathways, respectively. BXXXD exhibited its potential in
treating DCD by controlling synaptic plasticity and conduction, suppressing apoptosis, reducing
inflammation, and acting as an antioxidant. In a high glucose (HG) environment, the expression of
JNK, Foxo3a, SIRT1, ATG7, Lamp2, and LC3 was downregulated. BXXXD intervention on
HT22 cells potentially involved inhibiting excessive oxidative stress, promoting neuronal autophagy,
and increasing the expression levels of JNK, SIRT1, Foxo3a, ATG7, Lamp2, and LC3. Furthermore,
the neuroprotective effect of BXXXD was partially blocked by SP600125, while quercetin
enhanced the favorable role of BXXXD in the HG environment.Conclusion:BXXXD exerts its effects on DCD through multiple components, targets, levels, and
pathways. It modulates the JNK/SIRT1/Foxo3a signaling pathway to mitigate autophagy inhibition
and apoptotic damage in HT22 cells induced by HG. These findings provide valuable perspectives
and concepts for future clinical trials and fundamental research.