Chemical Composition and Mechanism of Zuoci Pill in Treating Perimenopausal Hearing Loss Based on Network Pharmacology and Molecular Docking Technology

Background In recent years, the symptoms of perimenopausal hearing loss (PMS-HL) have received widespread attention, but there is no targeted treatment. Zuoci pill has been used clinically for a hundred years, but there is no relevant research on the treatment of PMS-HL with this drug. Objective To explore the mechanism and therapeutic targets of Zuoci pill on PMS-HL through further validation of animal experiments based on the network pharmacology and molecular docking technology. Methods The active components and action targets of Zuoci pill were obtained through TCMSP and Uniprot databases, and the protein targets of PMS-HL were obtained through GeneCards, OMIM, TTD, DrugBank, and PharmGKB databases according to the composition of Zuoci pill from inception to February 2023, the intersection was taken to screen the potential therapeutic targets of Zuoci pill for the treatment of PMS-HL, and the "drug-active ingredient-target" interaction network diagram was constructed. The protein interaction analysis function of the String database was utilized to screen core targets. The Metascape database was used for enrichment analysis of the function of the proteins and pathways. Molecular docking of the core proteins was performed using Autodock and Pymol software to determine the binding capacity between key active ingredients and core targets. The menopausal animal model was established from September 2022 to January 2023, including Sham operation group (SHAM) group, ovariectomized (OVX) group, and Zuoci pill (ZCW) group, and serum level of the key protein interleukin 1β (IL-1β) was detected and statistically analyzed using SPSS 26.0. Results There were 90 active components, 226 potential protein targets, 2 481 PMS-HL related targets, and 150 Zuoci pill and PMS-HL intersection targets for the compounds in the Zuoci pill formula. A total of 183 items for biological process, 103 items for molecular function, and 103 items for cellular components were obtained in the Gene Ontology (GO) function. The top three Kyoto Encyclopedia of Genes and Genomes (KEGG) were cancer pathways, lipid and atherosclerotic lesion pathway, and receptor activation pathway for chemical carcinogenesis. Molecular docking showed that the main active ingredients of Zuoci pill in treating PMS-HL were quercetin, kaempferol, stigmasterol, β- Sitosterol, isorhamnetin, diosgenin, tetrahydrostilbene and kaempferone; the active components of Zuoci pill can bind to the core target proteins of serine/threonine kinase 1 (AKT1), cellular tumor antigen p53 (TP53), interleukin 6 (IL-6), vascular endothelial growth factor (VEGFA), cystatinase 3 (CASP3), IL-1β, epidermal growth factor receptor (EGFR), and estrogen receptor 1 (ESR1) stably. Comparison of serum IL-1β level among the three groups of rats showed statistically significant difference (F=11.73, P