Deciphering the Multi-Targeted Anti-Cancer Mechanisms of Lagenaria siceraria (Bottle Gourd) via Integrated Network Pharmacology and Molecular Docking: Inhibition of the PI3K-Akt Signalling Pathway

Abstract

Background: Cancer remains a major cause of global mortality, driven by complex genetic alterations and environmental stimuli. Lagenaria siceraria (bottle gourd) has long been used in traditional medicine because of its diverse pharmacological properties In this work, we use an integrated network pharmacology and molecular docking strategy to clarify the bioactive constituents and molecular targets of L. siceraria in cancer treatment.
Methods: Bioactive phytoconstituents of L. siceraria were screened, and their possible protein targets were determined through comprehensive databases. A protein-protein interaction (PPI) network was generated using STRING v11.0 and analyzed in Cytoscape to determine hub genes. Functional enrichment analyses were carried out with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. ADME prediction was used to evaluate drug-likeness and pharmacokinetic characteristics. Finally, molecular docking simulations were performed against the high-degree hub target AKT1 (PDB ID: 3O96) to assess binding affinities relative to the reference drug doxorubicin.
Results: Network analysis identified three main bioactive compounds-quercetin, beta-sitosterol, and oleanolic acid—that interact with 73 protein targets. The PPI network (73 nodes, 513 edges) and KEGG analysis indicated that these compounds mainly affect the PI3K–Akt signaling pathway, together with pathways involved in cancer and EGFR tyrosine kinase inhibitor resistance. Molecular docking showed that beta-sitosterol has a higher binding affinity to AKT1 of -11 kcal/mol, supported by a strong network of hydrogen bonds and hydrophobic interactions (Trp80, Val270, Leu210), which is greater than the affinity of doxorubicin (-10.6 kcal/mol). ADME analysis further confirmed favorable drug-likeness, although the high lipophilicity indicates that optimized delivery systems will be required.
Conclusion: These findings indicate that Lagenaria siceraria produces strong anti-cancer effects via a multi-component, multi-target mechanism, particularly through inhibition of AKT1-mediated cell survival. The results also offer a mechanistic basis for developing L. siceraria-derived phytochemicals as new therapeutic agents for oncology.