HSP90AB1‐Mediated Ubiquitin‐Proteasome Degradation of ITGBL1 Promotes Osteosarcoma Progression by Inhibiting Endoplasmic Reticulum Stress‐Induced Autophagy

ABSTRACT Osteosarcoma (OS) is one of the most malignant bone tumors in children and adolescents, but the molecular mechanisms of OS progression remain largely undefined. In this study, we demonstrate that Integrin subunit beta‐like 1 (ITGBL1) is downregulated in OS tissues, and its downregulation correlates with poor prognosis in OS patients. Functional assays revealed that ITGBL1 inhibits OS cell growth, metastasis, and stemness, while promoting apoptosis. The in vitro and in vivo experiments further revealed that ITGBL1 activates endoplasmic reticulum (ER) stress by upregulating ROS, thereby triggering autophagy in OS cells. In addition, the downregulation of ITGBL1 in OS is partly attributed to the abnormal upregulation of HSP90AB1 (heat shock protein 90 alpha family class B1). Mechanistically, ITGBL1 interacts with HSP90AB1 which facilitates ITGBL1 degradation through K63‐linked ubiquitination. Finally, through virtual screening and Co‐IP, we identified ivermectin as a potent inhibitor of the HSP90AB1‐ITGBL1 interaction, and treatment with ivermectin dramatically inhibited OS progression in vivo. In conclusion, we uncover a novel mechanism that promotes OS progression and identify a new candidate drug for the treatment of OS.