Network Pharmacology-guided Identification of Therapeutic Targets and Pathways for Cancer Stem Cell Inhibition Across Multiple Cancer Types

Cancer stem cells (CSCs) are implicated in tumor initiation, therapeutic resistance and disease recurrence, making them critical targets for cancer treatment. In this study, a comprehensive network pharmacology-based framework was employed to identify natural phytochemicals that may inhibit CSC pathways across multiple cancer types. A curated set of 82 anticancer phytochemicals was screened for drug-likeness using absorption, distribution, metabolism, excretion and toxicity profiling and physicochemical properties, which led to the selection of 10 promising candidates. These compounds were subjected to target prediction analysis, resulting in 916 potential targets, of which 493 overlapped with known cancer-related genes. Gene ontology (GO) enrichment analysis revealed that these overlapping genes were significantly involved in biological processes such as cellular metabolism, stress response and catabolic regulation, all of which are crucial to CSC maintenance. The cellular component and molecular function analyses supported their role in exosome signaling, protein interaction and transcriptional regulation. KEGG pathway analysis highlighted enrichment in critical CSC-associated signaling cascades, including PI3K-Akt, MAPK, cytokine interactions and NF-[Formula: see text]B pathways. Moreover, protein–protein interaction (PPI) network analysis identified 10 hub genes, seven of which (TNF, IL6, STAT3, SRC, EGFR, CASP3, PTGS2) showed significant association with poor survival outcomes based on Kaplan–Meier analysis. Molecular docking and dynamic simulation further validated strong and specific binding of phytochemicals, especially Rosmarinic acid, Catechin and Shikonin, against key targets (IL6, STAT3 and EGFR), suggesting their role in CSC inhibition. Overall, this integrative study highlights the potential of selected phytochemicals as multi-target therapeutic candidates capable of modulating CSC-associated networks and pathways.