Dihydrotanshinone I Targets MIF to Inhibit GSK ‐3β/β‐Catenin Axis‐Mediated Invasion and Metastasis in Gastric Cancer

Salvia miltiorrhiza Bunge has been a commonly used medicinal herb in China since ancient times, widely employed to treat blood stasis-related disorders, including cardiovascular and inflammatory diseases. Dihydrotanshinone I (DHT), a lipophilic diterpenoid derived from its roots, has demonstrated anti-tumor potential; however, its specific molecular mechanisms involved in gastric cancer (GC) metastasis remain a mystery. Here, we report that DHT significantly suppresses the invasion and metastasis of GC by directly targeting macrophage migration inhibitory factor (MIF). Using limited proteolysis-mass spectrometry (LiP-MS), we identified MIF as a direct binding target of DHT, which was further validated by surface plasmon resonance and molecular docking. Mechanistically, DHT binding to MIF restored GSK-3β activity, promoted β-catenin phosphorylation (Ser33/37/Thr41), and facilitated its proteasomal degradation, thereby inhibiting β-catenin nuclear translocation and transcription of epithelial-mesenchymal transition-related genes. In vivo experiments confirmed that DHT markedly suppressed peritoneal metastasis of GC. These findings not only elucidate a novel molecular axis-DHT/MIF/GSK-3β/β-catenin-in suppressing GC metastasis but also provide a mechanistic basis for the ethnopharmacological application of Danshen in cancer-related disorders. Furthermore, our findings raise the hypothesis that MIF might serve as a potential predictive biomarker for DHT treatment response in GC, a concept that warrants future clinical validation.