Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality globally. Even with significant advances in the synthesis of chemically based anti-cancer drugs, the unfavorable prognosis of the disease continues to pose a significant challenge. The most frequently encountered limitation of standard cancer treatments is drug resistance. Furthermore, newer target-specific therapies such as immunotherapy and stem cell therapy are costly enough and beyond the reach of most patients. Natural products, being affordable and less toxic, offer multi-targeted strategies to overcome drug resistance and improve therapeutic outcomes. Therefore, this study aims to investigate the therapeutic potential of glycoside compounds derived from Moringa oleifera: Niazirinin (NZR), Niazimicin A (NZA), 4-(Rhamnosyloxy) phenylacetonitrile (RPA), and Moringyne (MRG) in the context of CRC. An integrative network pharmacology strategy was used with the help of multiple databases and web tools. Glycoside compounds derived from Moringa oleifera were selected from the IMPPAT 2.0 database. Compound-target prediction was performed with Super Pred and STRING, while colorectal cancer (CRC)-associated genes were retrieved from the Gene Cards database. Overlapping genes between the compounds and CRC were determined with Venny 2.1. Protein-protein interaction (PPI) enrichment and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out with the STRING database (v12.0). Network building and identification of hub genes were carried out in Cytoscape (v3.10.3) and Cyto Hubba plugin respectively. Validation of the hub genes included mRNA expression profiling, overall survival, and tumor stage-specific analysis using GEPIA 2 webserver. Lastly, molecular docking of Moringa oleifera glycosides with the key hub CRC proteins was performed using the CB-Dock2 web server. Eleven hub genes (NFKB1, PIK3R1, PIK3CD, PIK3CB, CHUK, GRB2, NOS2, SLC2A1, ABL1, PDGFRA, and STAT1) were identified. Five major pathways, PI3K-Akt, cAMP, Ras, HIF-1 signaling, and MicroRNAs in cancer were highly enriched. Of the eleven hub genes, six (PIK3R1, NOS2, SLC2A1, ABL1, PDGFRA, and STAT1) were significantly dysregulated in colon (COAD) and rectal (READ) cancer tissues. In particular, NOS2, SLC2A1, and STAT1 were significantly upregulated, and PIK3R1, ABL1, and PDGFRA were significantly down regulated, indicating possible oncogenic and tumor-suppressive functions, respectively. Stage-specific analysis identified that expression of SLC2A1 differed significantly among pathological stages (F = 4.31, p = 0.00531), which warrants its consideration as a stage-specific prognostic biomarker. Molecular docking revealed that NOS2 and SLC2A1 exhibited high-affinity interactions with all Moringa oleifera glycosides, suggesting their potent inhibitory potential against metabolic and inflammatory targets in CRC. NOS2 and SLC2A1 emerged as key upregulated hub genes in CRC, showing strong binding affinities with all selected Moringa oleifera glycosides, demonstrating their therapeutic potential. Notably, SLC2A1 also presented stage-specific expression, highlighting its potential as a stage specific prognostic biomarker. Additionally, PDGFRA, a downregulated hub gene, demonstrated strong interactions and may serve as a tumor suppressive target modulated by these glycosides. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00461-y.