Bavachinin Suppresses Growth and Metastasis of Oral Squamous Cell Carcinoma through GSK-3β/β-Catenin Pathway: Potential for Synergistic Anticancer Therapy with Cisplatin

Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with poor prognosis, often complicated by recurrence, metastasis, and chemoresistance. While cisplatin remains a cornerstone of OSCC treatment, its efficacy is limited by systemic toxicity and resistance. In search of safer, effective adjunctive strategies, we investigated bavachinin, a flavanone from Psoralea corylifolia L., for its antitumor potential in OSCC. Integrated in vitro, in silico, and in vivo approaches were employed. Functional assays evaluated cell viability, apoptosis, migration, and invasion. Transcriptomic profiling identified dysregulated pathways, with key targets validated by quantitative reverse transcription PCR (qRT-PCR). Molecular docking predicted protein targets, confirmed by Western blot. Toxicity and therapeutic efficacy were evaluated in C57BL/6 mice and OSCC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Bavachinin significantly reduced cell viability, induced G2/M phase arrest, promoted apoptosis, and inhibited migration and invasion in OSCC cells. Transcriptomic profiling and qRT-PCR revealed suppression of genes involved in extracellular matrix remodeling and cell adhesion. Glycogen synthase kinase-3β (GSK-3β) was identified as a potential target by molecular docking analysis, confirmed by increased phosphorylation at Tyr216 and β-catenin degradation, leading to downregulation of matrix metalloproteinase-2 and fibronectin. As natural compounds are rarely used as monotherapies, bavachinin combined with cisplatin showed synergistic antitumor effects in OSCC CDX and PDX models, without systemic toxicity in mice. Bavachinin exerts potent antitumor effects via modulation of the GSK-3β/β-catenin pathway and may serve as a promising adjunct to cisplatin in OSCC treatment. • Bavachinin inhibits proliferation and induces G2/M arrest and apoptosis in OSCC. • It inhibits OSCC metastasis via ECM remodeling and adhesion gene suppression. • Bavachinin activates GSK-3β and facilitates β-catenin degradation in OSCC cells. • It synergizes with cisplatin to inhibit tumor growth in vivo without toxicity.