Exploring phytochemical inhibitors of fatty acid elongase ELOVL6 for targeted treatment of chronic myeloid leukemia: A comprehensive network-based drug discovery approach.

Quiescent leukemic stem cells (LSCs) that persist in the bone marrow microenvironment are responsible for chronic myeloid leukemia (CML) relapses and tyrosine kinase inhibitors (TKIs) resistance. This highlights a critical need to uncover alternative gene targets and pathways involved in LSC maintenance. Network biology in drug development has become essential for predicting drug targets in CML disease. This present computational study aims to identify key regulatory genes that are differentially expressed and involved in molecular pathway alternative to BCR-ABL, which may facilitate the eradication of leukemic stem and progenitor cells. Comparative analysis between CML stem and progenitor cells and their normal counterparts revealed 182 differentially expressed genes (DEGs). Applying Weighted Gene Co-expression Network Algorithm (WGCNA) identified a significant gene module comprising 73 hub genes. Protein-protein interaction and enrichment analyses indicated these genes are involved in mitochondrial translation elongation, steroid metabolism, cholesterol, and fatty acyl-CoA biosynthesis. Furthermore, a three-node regulatory network composed of hub genes, CML-associated transcription factors (TFs), and differentially expressed microRNAs (DEMs) was constructed, highlighting three key regulators: ELOVL6, SP1 (TF), and miR-1207-5p. To explore the therapeutic potential of the overexpressed target gene ELOVL6, we performed high-throughput virtual screening of phytochemical compounds against the ELOVL6 protein structure. Subsequent molecular docking, pharmacokinetics, toxicity, and molecular dynamics (MD) simulations revealed two phytochemicals - withaphysalin A and chelidimerine -as potential inhibitors of the ELOVL6 therapeutic biomarker in CML.