To study the protective effect of cerebroprotein hydrolysate and its related mechanism of regulating endoplasmic reticulum stress in ischemic stroke based on network pharmacology and animal experiments.

GeneCards and OMIM databases were used to screen the targets related to ischemic stroke and endoplasmic reticulum stress, and Wayne diagram was drawn to get the intersection genes. The protein-protein interaction network diagram was downloaded from String database and visualized by Cytoscape software, and the top 10 genes were screened by cytoHubba plug-in. Finally, Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） were enriched and analyzed. Mouse models of ischemic stroke were made by the suture-occluded method, and randomly divided into sham group, model group, cerebroprotein hydrolysate 0.2 g·kg^-1 group and 0.5 g·kg^-1 group, and edaravone 8 mg·kg^-1 group,with 11 mice in each group. The drug was administered continuously for 5 days after operation. The volume of cerebral infarction was measured by TTC staining, the contents of interleukin （IL）-6, IL-1β, γ-interferon （IFN-γ） and brain-derived neurotrophic factor （BDNF） in cerebral ischemic penumbra and serum were measured by ELISA, and the expression of Caspase-3 and AKT protein in brain tissue was observed by immunohistochemistry.

According to the results of network pharmacology, 41 intersection genes of ischemic stroke and endoplasmic reticulum stress were screened, and the top 10 genes screened were IL-6, ALB, INS, TNF, AKT1, CASP3, MAPK3, TP53, SIRT1 and VEGFA, respectively. GO enrichment resulted in 515 related entries. KEGG pathway enrichment involved lipid and atherosclerosis pathway, human cytomegalovirus infection, Alzheimer’s disease, phosphatidylinositol -3- kinase/ protein kinase B （PI3K/AKT） signaling pathway and so on. Compared with the model group, the cerebral infarction volume was significantly reduced （P<0.01）; the contents of IL-6, IL-1β and IFN-γ in serum and penumbra were decreased significantly （P<0.05）, and the contents of BDNF in serum and penumbra were increased significantly （P<0.05）; the expression of Caspase-3 in brain tissue was decreased significantly （P<0.05）, and the expression of AKT was increased significantly （P<0.05） in the two groups of cerebroprotein hydrolysate.

Based on the analysis of network pharmacology, the endoplasmic reticulum stress mechanism of ischemic stroke may be related to inflammation and apoptosis. The neuroprotective mechanism of cerebroprotein hydrolysate may be related to activating BDNF/PI3K/AKT pathway and inhibiting inflammation and apoptosis.