Potential molecular targets and pathways of Zingiber officinale in estrogen receptor-positive breast cancer: An integrated network pharmacology and molecular docking study

Abstract

Breast cancer remains a major global health burden, and the multi-target anti-cancer mechanisms of Zingiber officinale against estrogen receptor-positive (ER+) breast cancer require further clarification. This study employed an integrative approach combining network pharmacology and molecular docking to systematically investigate the anti-breast cancer mechanisms of Z. officinale. Ginger rhizome ethanol extract was profiled using LC–MS/MS to identify bioactive compounds. Putative compound targets were predicted using PubChem and SwissTargetPrediction, while ER+ breast cancer-related genes were retrieved from GeneCards. Overlapping targets were identified and subjected to GO/KEGG enrichment analysis, followed by protein-protein interaction (PPI) network construction using STRING, network visualization in Cytoscape, and hub-gene identification using CytoHubba. Molecular docking was then performed using CB-Dock2/AutoDock Vina against key hub proteins, with tamoxifen, doxorubicin, and 5-fluorouracil used as reference drugs. Nine bioactive compounds were identified. Target prediction identified 445 potential protein targets for ginger compounds and 10,003 ER+ breast cancer-related genes, with Venn diagram analysis revealing 266 overlapping targets representing therapeutic intervention points. KEGG pathway enrichment identified 20 significantly enriched pathways (false discovery rate less than 0.05), including EGFR tyrosine kinase inhibitor resistance, estrogen signaling, PI3K-Akt signaling, and MAPK signaling pathways. PPI network analysis identified ten hub genes: AKT1, GAPDH, SRC, STAT3, EGFR, ESR1, PPARG, MAPK3, MMP9, and TLR4. Adenosine demonstrated exceptional affinity to GAPDH (-9.0 kcal/mol), approaching that of tamoxifen (-8.9 kcal/mol). 6-Gingerol demonstrated strong binding to MMP9 (-7.9 kcal/mol), ESR1 (-7.6 kcal/mol), and MAPK3 (-7.6 kcal/mol). Detailed interaction analysis revealed that the adenosine-GAPDH complex formed multiple hydrogen bonds with THR65, ARG15, GLU17, THR87, and ASN239, with extensive hydrophobic contacts stabilizing the complex within the glycolytic active site. These findings provide mechanistic insights supporting ginger's therapeutic potential as a complementary natural product in ER-positive breast cancer management and identify specific molecular targets for future preclinical and clinical investigations.