Triptolide Suppresses Tongue Squamous Cell Carcinoma Progression via PI3K-AKT Pathway Inhibition: An Integrative...

Tongue squamous cell carcinoma, the most aggressive subtype of oral squamous cell carcinoma, which is associated with high mortality, frequent recurrence, and early lymph-node metastasis. Triptolide, a bioactive diterpenoid from Tripterygium wilfordii, exhibits broad anticancer activity. Although its inhibitory action on OSCC has been established, its specific molecular regulatory mechanisms in TSCC, a distinct and aggressive subtype, remain largely underexplored. The present study investigates the regulatory role of triptolide in the PI3K-AKT signaling pathway, which is a critical axis intimately linked to tumor survival and metastasis. A network-pharmacology workflow was used to intersect triptolide putative targets with TSCC-related genes. Core hubs were identified with Cytoscape; KEGG and GO analyses highlighted the PI3K-AKT axis as the top enriched pathway. Binding kinetics were quantified by molecular docking and surface plasmon resonance (SPR). Cellular assays (CCK-8, Transwell, wound-healing, Western blot and immunofluorescence) validated the predictions. We retrieved 389 common targets and shortlisted eight key nodes (JUN, MAPK1, MAPK3, AKT1, TP53, BCL2, STAT3, MYC). SPR revealed high-affinity binding of triptolide to AKT1 and PI3K. Functionally, triptolide dose-dependently suppressed TSCC cell proliferation, invasion, and migration, downregulated PI3K-AKT signaling proteins, and reduced the colocalization and phosphorylation levels of p-PI3K and p-AKT. This study is the first to demonstrate the pivotal role of the PI3K-AKT signaling pathway in mediating the antitumor effects of triptolide in tongue squamous cell carcinoma. Our findings thereby provide a novel theoretical foundation for the development of traditional Chinese medicine-based therapeutic strategies targeting this malignancy.