Triptonide (TN), a natural bioactive compound derived from Tripterygium wilfordii with multiple antitumor activities, has a poorly defined exact mechanism in acute myeloid leukemia (AML)—a hematologic malignancy with limited treatment options. This study systematically clarifies TN’s mechanisms in AML through an integrative strategy combining network pharmacology, molecular docking, molecular dynamics simulation, and in vitro/in vivo experiment validation. Predicted TN targets using Swiss Target Prediction and PharmMapper, and AML-associated genes via GeneCards, OMIM, and CTD. Verall, O198 overlapping targets were mapped to build a PPI network using STRING and Cytoscape. Identified hub gene (AKT1, EGFR, HSP90AA1, HSP90AB1, and PIK3R1) using CytoNCA, MCODE, and CytoHubba algorithms. GO and KEGG enrichment analyses highlighted marked enrichment in the PI3K/AKT pathway. TN exhibited high affinity binding to AKT1 (−7.28 kcal/mol) and PIK3R1 (−7.33 kcal/mol), with stable interactions confirmed by molecular dynamics simulations. The GSEA of the DEGs from GEPIA 2 revealed prominent activation of the PI3K/AKT signaling pathway, indicating its key role as a regulator of AML pathogenesis. In vitro, TN dose-dependently suppressed proliferation of multiple AML cell lines induced apoptosis, and downregulated the expression of P-PI3K and P-AKT. The AKT activator SC79 reversed TN-induced suppression in AML cells, validating PI3K/AKT pathway dependency. In vivo, TN significantly inhibited tumor growth in xenograft models without causing organ toxicity in female nude mice. These findings reveal the therapeutic potential of TN against AML through inhibiting the PI3K/AKT axis. With no PI3K/AKT inhibitors targeting AML approved as first-line therapies, TN emerges as a promising candidate for AML treatment, offering a safer natural alternative.
Song et al. (Tue,) studied this question.