Network Pharmacology and Computational Study to Identify Active Components and Potential Targets of Polygonatum...

Polygonatum sibiricum (P. sibiricum) possesses antioxidant and antiinflammatory activities. We explored the multi-target mechanisms of P. sibiricum against hepatocellular carcinoma (HCC), aiming to improve its poor prognosis.

Active compounds and disease targets of P. sibiricum were retrieved from the TCMSP and CTD databases. A PROTEIN-PROTEIN INTERACTION (PPI) network was constructed using the STRING database, and functional enrichment was performed with the clusterProfiler package. A compound-target-pathway network was developed in Cytoscape. Immune infiltration was assessed via CIBERSORT and ESTIMATE algorithms, while ligand-target binding was evaluated by molecular docking and 100-ns molecular dynamics (MD) simulations. In vitro experiments were performed to explore the expression and functions of the key genes.

We screened 9 active components, 87 putative targets, and 240 HCC-related genes. 20 overlapping targets were used to construct a PPI network. Network analysis identified baicalein and 4 core targets (MMP9, AKT1, TP53, and PTGS2). Molecular docking and 100-ns MD simulations confirmed stable ligand-protein binding. Immune profiling showed that higher expression of the core targets was related to higher StromalScore, ImmuneScore, and lower tumor purity. Enrichment analysis revealed that these genes were involved in critical pathways, including angiogenesis, EMT, and inflammation response. Functionally, MMP9 knockdown suppressed HCC cell proliferation, migration, and invasion.

P. sibiricum, particularly through baicalein targeting FOS/MMP9/AKT1/ TP53/PTGS2, inhibited HCC development by modulating EMT/angiogenesis pathways and immune milieu. However, these findings required further verification.

Baicalein was identified as an active compound targeting 5 crucial genes to suppress HCC progression, uncovering a new anti-HCC mechanism of P. sibiricum.