Rorγ Targeting Promotes Apoptosis and Ferroptosis in Osteosarcoma by Reprogramming Mitochondrial Oxidative Phosphorylation

Osteosarcoma (OS) is the most common primary malignant bone tumor with poor prognosis. The treatment strategy has remained virtually unchanged over the past 40 years. Here, we show that nuclear receptor RORγ may serve as a potential therapeutic target in osteosarcoma. OS exhibits hyper-activated OXPHOS program which fuels the carbon source to promote tumor progression. We find that RORγ is overexpressed in OS tumor sample and cell lines and is linked to hyper-activated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate OXPHOS program via upregulating the expression of respiratory chain components genes. Genetic knock-down and pharmacological inhibition of RORγ strongly inhibit OXPHOS activation, dysregulate mitochondrial functions, increase ROS production, and result in OS cell apoptosis and ferroptosis. RORγ antagonists strongly suppressed OS tumor growth in multiple cell-based xenograft models and human patient-derived xenograft (PDX) models, and sensitize OS tumors to chemotherapy, without obvious toxicity in mice. Taken together, our results indicate that RORγ is a master regulator of the OXPHOS program and could provide a novel therapeutic strategy for OS.