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INTERNATIONAL CONGRESS OF

CancerGenetics

• A Network Pharmacology Investigation into the Multi-Target Mechanisms of Withalongolide A Against Pancreatic Cancer

• Mohammadreza Mehraban,^1,* Sara Gholami,² Amirsajad Jafari,³
  1. Babol Branch. Islamic Azad University, Babol, Iran
  2. Babol Branch. Islamic Azad University, Babol, Iran
  3. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  
  
  
• Introduction: Pancreatic cancer remains one of the most lethal malignancies, characterized by aggressive progression and profound therapeutic resistance. Natural compounds offer a promising avenue for novel drug discovery, with Withalongolide A demonstrating significant anti-cancer potential. However, the complex molecular mechanisms underlying its effects are not fully elucidated. This study employs a network pharmacology approach to systematically identify the key targets, biological pathways, and interaction networks modulated by Withalongolide A to uncover the basis for its potential therapeutic activity against pancreatic cancer.
• Methods: We identified potential protein targets of Withalongolide A and known pancreatic cancer-associated genes using swisstargetprediction and Diginet databases, respectively. The overlapping genes were selected as core targets for constructing a protein-protein interaction (PPI) network via the STRING database. Subsequently, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to determine the primary biological processes and signaling pathways involved. The network was then imported into Cytoscape for topological analysis to identify central hub genes.
• Results: The KEGG pathway enrichment analysis further solidified the critical cancer-associated functions of the gene set, identifying highly specific and significant dysregulation in three oncogenic pathways. The most significantly enriched pathway was the Hedgehog signaling pathway (FDR = 4.0e-08), a key regulator of cell proliferation and differentiation often activated in cancers. This was followed by enrichment in the p53 signaling pathway (FDR = 5.0e-07), indicating a pivotal role in the cellular response to DNA damage and apoptosis, a process almost universally altered in tumorigenesis. Finally, the enrichment for MicroRNAs in cancer (FDR = 7.0e-06) suggests post-transcriptional regulatory mechanisms contribute to the observed phenotype, potentially influencing the expression of oncogenes and tumor suppressors. The exceptional statistical significance of these findings, particularly for Hedgehog and p53 signaling, underscores that the gene set is not merely related to general cellular processes but is directly and centrally involved in the core molecular pathways that drive cancer development and progression. The Cytoscape network analysis revealed MDM2 and SMO are hub genes, which hold the network together. Attached to these hubs are several functional modules (evidenced by high clustering coefficients), such as CDK6 and RCHY1
• Conclusion: This network pharmacology analysis provides a novel, systems-level insight into the mechanisms driving the anti-cancer effects of Withalongolide A. Our findings suggest its efficacy relies not on a single target but on the comprehensive modulation of a complex protein network central to pancreatic cancer's core pathology. The identification of the Hedgehog and p53 signaling pathways as the most significantly enriched functions underscores the compound's potent role in disrupting fundamental cancer processes, including cell proliferation, differentiation, and apoptosis. The network's structural reliance on the two main hubs, MDM2 and SMO, pinpoints them as potential mediators of Withalongolide A's therapeutic action. Furthermore, the involvement of functional modules centered around proteins like RCHY1 indicates that the regulation of protein degradation and cell cycle control are key downstream effects. Collectively, these findings provide a strong scientific rationale for the further development of Withalongolide A as a potential therapeutic agent for pancreatic cancer and highlight MDM2 and SMO as primary targets for future experimental validation.
• Keywords: MDM2, SMO, Natural Compounds, Drug Discovery