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

ABSTRACT

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.