Isoliquiritigenin in breast cancer therapy: from mechanistic insights to advanced nano-enabled delivery strategies.

Isoliquiritigenin (ISL), a chalcone from Glycyrrhiza species, exhibits multi-target anti-breast cancer activity but faces pharmacokinetic limitations. This review synthesizes evidence for ISL's molecular targets and mechanisms and evaluates nano-delivery strategies. In preclinical models, ISL inhibits proliferation via miR-374a/PTEN/Akt, reverses EMT through miR-200c/C-JUN/β-catenin, targets cancer stem cells via GRP78 inhibition and WIF1 reactivation, suppresses aromatase and COX-2, modulates osteoclast activity, and reprograms glycolysis and tryptophan metabolism. Independent groups demonstrated brain metastasis inhibition via circNAV3/EGFR, immune enhancement through PD-L1 reduction, and tryptophan reprogramming via IRF5/SLC7A5/IDO1. Systematic reviews consolidated evidence across 33 studies. TNBC is the most promising preclinical indication, with ER + breast cancer a potential target. Four nanoformulation platforms have been developed to overcome low bioavailability, rapid Phase II metabolism, and short half-life. Molecular docking predicts binding to PTEN, GRP78, β-catenin, and COX-2 but requires biophysical validation. Critical gaps remain: key mechanisms need independent validation, nanoformulation data derive mainly from one group, and no nano-ISL has entered clinical trials. This review provides a hypothesis-generating framework prioritizing mechanistic replication, scalable GMP production, GLP-compliant toxicology, and qualified biomarkers.