Abstract BACKGROUND Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality globally. This study investigates the therapeutic potential of glycoside compounds derived from Moringa oleifera leaves: Niazirinin (NZR), Niazimicin A (NZA), 4-(Rhamnosyloxy)phenylacetonitrile (RPA), and Moringyne (MRG) in the context of CRC. METHODS An integrative network pharmacology strategy was used including compound-target prediction, protein–protein interaction (PPI) analysis, and Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Eleven hub genes (NFKB1, PIK3R1, PIK3CD, PIK3CB, CHUK, GRB2, NOS2, SLC2A1, ABL1, PDGFRA, and STAT1) were identified. Additional validation involved mRNA expression profiling, overall survival analysis, and tumor stage-specific expression analysis. Lastly, molecular docking was conducted to assess the binding affinity of the glycosides with major CRC regulatory proteins. RESULTS 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 showed NOS2 and SLC2A1 have high-affinity interaction of NZR and MRG (–8.6 kcal/mol), positing potent inhibitory activity against CRC metabolic and inflammatory targets. CONCLUSION This integrated analysis presents the therapeutic potential of Moringa oleifera glycosides, particularly NZR and MRG, as novel multi-target therapeutic drugs for the treatment of CRC. SLC2A1 and NOS2 genes as hub genes represent therapeutic targets worth considering in further preclinical and clinical studies. Graphical Abstract
Sharma et al. (Fri,) studied this question.