Exploring the potential mechanism of ginsenoside Rg1 to regulate ferroptosis in Alzheimer's disease based on network pharmacology.

Objectives: To explore the pathogenesis of Alzheimer's disease (AD), the potential targets and signaling pathways of ginsenoside Rg1 against AD were investigated by network pharmacology.

Methods: Ginsenoside Rg1 targets were identified through PubChem, PharmMapper, and Uniprot databases, while the GeneCards database was used to examine the respective targets of amyloid precursor protein (APP) and AD. Then, the common targets between ginsenoside Rg1 and APP were explored by the Venny tool, the interaction network diagram between the active components and the targets was built via Cytoscape software, as well as GO enrichment and KEGG pathway annotation analysis were performed. Furthermore, genes associated with ferroptosis were found by the GeneCards and FerrDb databases. Besides, the connection among ginsenoside Rg1, APP, ferroptosis, and AD was predicted and analyzed. Finally, the effects of ginsenosides Rg1 and liproxstain-1 on the proliferation and differentiation of APP/PS1 mice were evaluated by immunohistochemistry.

Results: Ginsenoside Rg1, APP, ferroptosis, and AD had 12 hub genes. GO enrichment and KEGG pathway annotation analysis showed that EGFR, SRC, protein hydrolysis, protein phosphorylation, the Relaxin pathway, and the FoxO signaling pathway play an important role in the potential mechanism of ginsenoside Rg1's under regulation of ferroptosis anti-AD through the modulation of APP-related signaling pathways. The APP/PS1 mice experiment verified that ginsenosides Rg1 and liproxstain-1 can promote the proliferation and differentiation.

Conclusion: Ginsenoside Rg1, APP and ferroptosis may act on EGFR, SRC, the Relaxin and FoxO signaling pathways to regulate protein metabolism, protein phosphorylation and other pathways to improve AD symptoms.