Network pharmacology and molecular docking-based prediction of the multi-target mechanisms by which icariin intervenes in perimenopausal depressive-like symptoms

Background: Perimenopausal depressive-like symptoms are closely related to estrogen fluctuations, neuroinflammation and impaired neuroplasticity. Icariin has phytoestrogen-like and neuroprotective activities, but its multi-target mechanism in intervening in this pathological state remains unclear. Objectives: To predict the key targets and action pathways of icariin in intervening in perimenopausal depressive-like symptoms based on network pharmacology and molecular docking. Methods: Potential targets of icariin and targets related to the perimenopausal module and the depression module were obtained through public databases and drug-disease common targets were screened; a protein-protein interaction (PPI) network was constructed and core targets were screened; GO and KEGG enrichment analyses and integrated network analysis of "Icariin-common targets-pathways-disease" were performed; finally, molecular docking validation was carried out for the core targets. Results: A total of 219 potential targets of icariin were obtained and 74 common targets were identified after intersection with the disease modules. The PPI network contained 68 connected nodes and 387 interaction edges and AKT1, ESR1, TNF, IL6 and TP53 ranked in the top 5 by MCC. The common targets were significantly enriched in GO terms and the top 20 KEGG pathways (all adjusted P < 0.05), mainly involving regulation of protein phosphorylation, apoptotic process, steroid hormone response and the PI3K-Akt, MAPK, estrogen, TNF and neurotrophin signaling pathways. The integrated network included 96 nodes and 330 edges. The redocking RMSD values of the 9 core targets were all <2.00 A; the optimal docking binding energies of icariin with ESR1, PTGS2 and MAPK1 were -10.12, -9.28 and -8.76 kcal/mol, respectively. Conclusion: Icariin may take ESR1, AKT1, MAPK1 and PTGS2 as key nodes and synergistically intervene in perimenopausal depressive-like symptoms through estrogen regulation, inflammatory response regulation and pathways related to cell survival and apoptosis.