APMAdvances in Precision Medicine2424-85922424-9106WHIOCE PUBLISHING PTE. LTD.10.18063/APM.v11i5.2040ArticleNetwork Pharmacology-Based Investigation of the Mechanism by Which Sijunzi Decoction Modulates Microglial Activation and Improves Diabetic Cognitive Impairmenthttps://artdesignp.com/journal/APM/11/5/10.18063/APM.v11i5.2040RuanTian20261152026-05-26Diabetic cognitive impairment (DCI) is a chronic complication of type 2 diabetes mellitus (T2DM) in which persistent neuroinflammation driven by microglial activation plays a central pathogenic role. Sijunzi decoction (SJZD), a classical formula composed of Ginseng Radix et Rhizoma (Renshen), Atractylodis Macrocephalae Rhizoma (Baizhu), Poria (Fuling) and Glycyrrhizae Radix et Rhizoma Praeparata cum Melle (Gancao), has demonstrated cognition-improving activity in diabetic models, yet its molecular mechanism remains unclear. Using a fully reproducible network-pharmacology pipeline, we retrieved 136 active compounds of the four component herbs from TCMSP (oral bioavailability ≥ 30%, drug-likeness ≥ 0.18) and mapped them to 413 human protein targets via UniProt. Disease targets were obtained from the Open Targets platform: 2184 targets for cognitive impairment / Alzheimer disease and 1500 for T2DM. The intersection of SJZD targets with the cognitive-impairment gene set yielded 71 putative DCI targets. A STRING protein–protein interaction network (confidence ≥ 0.40) of these targets contained 71 nodes and 280 edges (density 0.113, 5 connected components); topology analysis identified GSK3B, CTNNB1, HIF1A, CREB1, CAV1, SLC2A4, BACE1, NOS3 and JAK2 as core hub genes. Enrichr-based Gene Ontology and KEGG analysis showed that these targets were significantly enriched in adenylate-cyclase-activating adrenergic receptor signaling, G-protein-coupled receptor signaling, the insulin resistance pathway (hsa04931), neuroactive ligand–receptor interaction (hsa04080), calcium signaling (hsa04020), the cholinergic synapse and the “neuroinflammation and glutamatergic signaling” WikiPathway. These results indicate that SJZD ameliorates DCI by simultaneously regulating insulin resistance, neurotransmission and neuroinflammation, processes intimately linked to microglial activation, thereby providing a mechanistic rationale and candidate targets for subsequent experimental validation.Sijunzi decoction,Diabetic cognitive impairment,Network pharmacology,Microglia; Insulin resistance,Neuroinflammation

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