Baicalein Synergizes with Docetaxel in TNBC and the Combination Suppresses AKT/GSK3β/β-Catenin Signaling

Limited docetaxel efficacy in triple-negative breast cancer (TNBC) necessitates chemosensitizers. Baicalein is a potential chemosensitizer, but its synergy with docetaxel in TNBC is unclear. Here, we investigated the combined effects and underlying mechanisms. The concentrations of baicalein (80 μM) and docetaxel (20 nM) were tested on TNBC cells; synergy was assessed by CCK-8 and Chou–Talalay analysis. Proliferation, migration, invasion, and apoptosis were assessed by colony formation, wound healing, Transwell, Matrigel, and flow cytometry assays. Protein levels of p-AKT, p-GSK3β and β-catenin were determined by western blot, and HSP90AA1 mRNA by qPCR. Baicalein–HSP90AA1 binding was analyzed by molecular docking. The prognostic value of HSP90AA1 was analyzed by Kaplan–Meier Plotter. The combination exhibited synergistic anti-tumor activity (CI < 0.9), significantly suppressed proliferation, migration and invasion, and enhanced apoptosis. Mechanistically, the combination reduced p-AKT, p-GSK3β, and β-catenin protein levels without affecting HSP90AA1 mRNA. Molecular docking indicated a potential interaction between baicalein and HSP90AA1. High HSP90AA1 expression correlated with shorter distant metastasis-free survival (HR = 1.71, p = 0.0046) and worse overall survival (HR = 2.15, p = 0.021). Thus, baicalein synergizes with docetaxel to suppress TNBC in vitro, accompanied by suppression of AKT/GSK3β/β-catenin signaling, potentially through interaction with HSP90AA1, a proposed upstream target.