FAK activation mediates IQGAP3-promoted lung metastasis in osteosarcoma

Osteosarcoma (OS), the most common primary malignant bone tumor, is characterized by a high metastatic propensity and poor survival, highlighting the urgent need to define the molecular drivers of its progression. Here, bioinformatics and clinical tissue analysis identified aberrantly high expression of IQGAP3 in osteosarcoma, with its protein level showing a significant negative correlation with patient prognosis. Functional assays demonstrate that IQGAP3 promotes OS cell migration and invasion in vitro and drives lung metastasis in vivo. Transcriptomic analysis links IQGAP3 to the Focal Adhesion Kinase (FAK) signaling pathway. Mechanistically, IQGAP3 directly interacts with FAK and enhances its phosphorylation at Tyr397. Pharmacological activation of FAK counteracts the suppression of migration and metastasis resulting from IQGAP3 knockdown both in vivo and in vitro. Conversely, FAK inhibition reduces phosphorylation of GSK3β at Ser9, thereby suppressing the GSK-3β/β-catenin axis. Furthermore, Wnt pathway inhibition attenuates IQGAP3-driven cell migration. Finally, we identify the transcription factor ZEB1 as a direct upstream regulator that binds to the IQGAP3 promoter and promotes its expression. Together, our results delineate a novel ZEB1/IQGAP3/FAK/β-catenin signaling axis that critically promotes OS lung metastasis, revealing a potential therapeutic target for intervention.