WITHDRAWN: Anti-Hepatocellular Carcinoma effect of Pien-Tze-Huang via multi-target regulation of PI3K/Akt Pathway inducing cell cycle arrest: from computational prediction to experimental validation

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Introduction Pien-Tze-Huang (PTH) has shown promising therapeutic effects on hepatocellular carcinoma (HCC). However, its mechanism of action remains unclear. This study aimed to illustrate the pharmacological mechanisms of action of PTH against HCC based on an integrated target prediction method, network pharmacology, molecular docking and in vitro experiments. Methods An integrated target prediction method was used to predict PTH's active compound-related targets and overlap them with HCC-related targets to identify potential therapeutic targets. Compounds-targets-disease network was constructed using Cytoscape for network topology analysis to identify key targets and key active compounds. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the key targets were conducted using the DAVID database. Molecular docking was employed to assess the binding affinity between key targets and PTH components, compared to FDA-approved drugs. In vitro experiments, including colony formation, CCK-8 cell viability assay, and Western blot analysis, were performed to further validate the findings. Results A total of 47 potential targets were identified, and network topology analysis revealed 10 key hub genes (including MMP9, MAP2K1, MET, NTRK1, NOS3, SLC2A1, ABCB1, FLT1, FGFR2, and AR) and 10 key compounds. GO enrichment analysis showed 253 biological processes, 36 cellular components, and 66 molecular functions. KEGG pathway analysis indicated that the anti-cancer effects of PTH are mainly mediated through multiple pathways, particularly the PI3K-Akt signaling pathway. Molecular docking analysis demonstrated that multiple PTH compounds exhibit significant binding affinity with several key targets, with binding affinity superior to that of FDA-approved anti-HCC drugs. In vitro experiments further validated that PTH significantly inhibits cell proliferation and induces apoptosis by suppressing the PI3K-Akt signaling pathway. Discussion This study, combining computational predictions and in vitro experimental validation, demonstrates that PTH exerts anti-HCC effects through coordinated multi-component and multi-target interactions, primarily by inhibiting PI3K-Akt pathway activation, thereby inducing apoptosis and blocking malignant proliferation.

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