Natural G-Quadruplex Stabilizers: A Targeted Strategy for Breast Cancer Therapy

G-quadruplexes (G4s) are non-canonical DNA structures that are important in gene regulation, telomere repair, and cancer. The G4s in breast cancer (BC) are enriched in the promoters of important oncogenes, such as c-MYC, KRAS, BCL2, HER2 , and ESR1 , which are good therapeutic targets. Although synthetic G4 stabilizers are well-researched, natural products are a poorly investigated source of selective ligands with good biocompatibility and multi-target properties. This review systematically collects and analyzes natural compounds, such as flavonoids, alkaloids, polyphenols, terpenoids, and organosulfur compounds, which exhibit G4-stabilizing effects, particularly their suitability in BC. We provide a comprehensive landscape approach to define interactions between G4-ligands, discuss how these interactions are stabilized (via π-π stacking, electrostatic interactions, and groove binding), and map these compounds to genomic regions associated with BC G4-formation. We also identify key research gaps that are essential, including limited in vivo validation, subtype-specific efficacy, and pharmacokinetic issues. The available evidence suggests that natural G4 stabilizers have potential as multi-target and biocompatible agents for BC therapy. However, their effectiveness is currently constrained by a shortage of thorough in vivo studies and subtype-specific data. Lastly, to incorporate in silico docking, mechanistic studies, and translational strategies, we present a prospective roadmap for drug discovery to bring natural G4 stabilizers targeting BC. The diagram illustrates the relationship between natural products, mechanisms, breast cancer oncogenes and the S cubed framework. Natural products include flavonoids, alkaloids, polyphenols, terpenoids and organosulfur. These are linked to mechanisms such as pi-pi stacking, electrostatic, hydrogen bonding and groove binding. These mechanisms connect to breast cancer oncogenes, including c-MYC, KRAS, BCL2, HER2, ESR1, VEGF and hTERT. The goal is to identify the best natural products for breast cancer G4s stabilization. The S cubed framework, described as a fail-early strategy, focuses on selectivity, stability and solubility.Diagram linking natural products, mechanisms, breast cancer oncogenes and S cubed framework for G4 stabilization.