Exploration of the Mechanism of Ginkgo biloba Leaves Targeted Angiogenesis against Gastric Cancer

Gastric cancer (GC), the fifth most prevalent malignancy worldwide, is the fifth leading cause of cancer-related deaths. Angiogenesis, the formation of new blood vessels from preexisting vasculature, plays a critical role in tumor growth, invasion, and metastasis, making it a primary target for cancer therapies. Despite advancements in conventional therapies, their limited efficacy and associated adverse effects necessitate alternative therapeutic strategies. Medicinal plant-derived agents, such as Ginkgo biloba leaves (GBLs), have garnered increased attention for their antitumor properties. However, their specific anti-GC mechanisms for targeting angiogenesis remain unclear. Presently, a comprehensive approach incorporating network pharmacology, pharmacokinetics, computational chemistry, bioinformatics analysis, and experimental validation was performed. Utilizing network pharmacology and pharmacokinetic analyses, 43 bioactive compounds and 852 potential targets are identified through ADME screening and the SysDT algorithm. Core angiogenesis-related genes (ARGs) are subsequently determined via integration of single-factor Cox regression, WGCNA, and LASSO methodologies. Intersection analysis of differentially expressed genes (DEGs) in GC patients, predicted GBLs targets, and ARGs identified four hub genes, i.e., EZH2, FEN1, TTF2, and UHRF1. Molecular docking and MD simulations confirmed the robust binding interactions between key compounds and these targets. Functional enrichment analysis revealed three critical pathways of GBLs in treating GC, which include the p53/p21 signaling, G1/S cell cycle transition, and Wnt/β-catenin signaling. In vitro studies demonstrate the antiproliferative and pro-apoptotic effects of EGb 761, showing the anti-GC effects of GBLs. This is the first comprehensive exploration of the anti-GC molecular mechanism of GBLs targeted angiogenesis employing the combination of dry and wet experiments. All the findings offer valuable insights into antiangiogenic mechanisms of GBLs in treating GC, providing a foundation for developing novel plant-based treatments for complex diseases.