Isoliquiritigenin in Breast Cancer: A Systematic Review of Its Preventive and Anti-metastatic Mechanisms.

Context: Breast cancer is the most prevalent malignancy among women globally, with metastasis significantly reducing survival rates. Isoliquiritigenin (ISL), a bioactive chalcone derived from Glycyrrhiza species, has shown promise in preclinical studies for its multifaceted anticancer properties, including modulation of metastatic processes. Objectives: This systematic review evaluates preclinical evidence on ISL's mechanisms in breast cancer prevention and metastasis suppression. Evidence Acquisition: Following PRISMA guidelines, a comprehensive search was conducted across PubMed/Medline, Scopus, Embase, and grey literature up to May 2025. Quality was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for in vitro studies and SYRCLE's Risk of Bias (RoB)/Animal Research: Reporting of in vivo Experiments (ARRIVE) for in vivo studies. Results: From 4,522 records, 33 studies (52 datasets: One in situ, 33 in vitro, 18 in vivo) met inclusion criteria. Most studies originated from China and Hong Kong, with robust methodological quality, though reporting on randomization and blinding were often unclear. The ISL demonstrated potent anticancer effects by: (1) Inducing apoptosis and autophagy via mechanistic target of rapamycin (mTOR) inhibition and disruption of arachidonic acid pathways; (2) modulating microRNAs (miRs; e.g., miR-374a, miR-200c) to suppress epithelial-mesenchymal transition (EMT); (3) altering hormone receptor [HR; ERα, breast cancer type 1 susceptibility protein (BRCA1)] expression and inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling; and (4) reducing angiogenesis [vascular endothelial growth factor (VEGF)/hypoxia-inducible factor-1 alpha (HIF-1α) suppression] and inflammation [cyclooxygenase-2 (COX-2)/nuclear factor-kappa B (NF-κB) inhibition]. Nanoparticle delivery systems (e.g., iRGD-targeted nanoparticles) enhanced ISL's tumor targeting and efficacy while maintaining low toxicity. Conclusions: Preclinical evidence highlights ISL's potential as a multi-target agent against breast cancer progression and metastasis. However, clinical trials are urgently needed to validate its efficacy, safety, and optimal delivery strategies in patients. Future research should prioritize translational studies and combinatorial therapies to bridge the gap between bench and bedside.