Exploring the immunomodulatory mechanisms of Astragalus membranaceus in esophageal cancer treatment through network pharmacology, molecular docking, and molecular dynamics simulation

Esophageal cancer (EC) is one of the most aggressive malignancies with limited therapeutic options and poor prognosis. Astragalus membranaceus (AM), a traditional Chinese herbal medicine with established immunomodulatory properties, has demonstrated anti-tumor potential, but its systematic immunomodulatory mechanisms in EC remain unclear. Here, we employed an integrative strategy combining network pharmacology, survival analysis, and molecular dynamics simulation to elucidate AM's immunotherapeutic mechanisms in EC. We identified 17 active compounds from AM and 445 target genes associated with them, Among these, 113 were classified as immune target genes (ITGs) with potential relevance to EC. Functional enrichment analysis revealed significant involvement of ITGs in TNF signaling, PI3K-AKT signaling, and PD-L1/PD-1 checkpoint pathways.The prognostic model constructed by five ITGs (AHR, AKT1, GPER1, IL4, and MAPK1) can be used as a reliable prognostic feature of EC and was validated in an independent cohort. Protein-protein interaction analysis identified eight core ITGs (TNF, RELA, IL6, NFKB1, JUN, AKT1, TP53, and IL1β) significantly associated with immune cell infiltration, immune checkpoint expression, and immunotherapy response. Molecular docking and molecular dynamics simulation confirmed stable binding of isorhamnetin to AKT1, revealing key interaction residues. These findings suggested the multi-compound, multi-target, and multi-pathway immunomodulatory mechanism of AM in EC, providing a prognostic tool for patient stratification and identifying the isorhamnetin-AKT1 axis as a potential therapeutic target.