Super-enhancer-driven MLX mediates redox balance maintenance via SLC7A11 in osteosarcoma

Abstract Osteosarcoma (OS) is a common type of bone tumor for which there has been limited therapeutic progress over the past three decades. The prevalence transcriptional addiction in cancer cells emphasizes biological significance and clinical relevance super-enhancers. In this study, we found that Max-like protein X (MLX), member Myc-MLX network, driven by Upregulation MLX predicts poor prognosis osteosarcoma. Knockdown impairs growth metastasis osteosarcoma vivo vitro. Transcriptomic sequencing revealed involved various metabolic pathways (e.g., lipid metabolism) can induce reprogramming. Furthermore, knockdown results disturbed transport storage ferrous iron, leading to an increase level cellular iron subsequent induction ferroptosis. Mechanistically, regulates glutamate/cystine antiporter SLC7A11 promote extracellular cysteine uptake required biosynthesis essential antioxidant GSH, thereby detoxifying reactive oxygen species (ROS) maintaining redox balance cells. Importantly, sulfasalazine, FDA-approved anti-inflammatory drug, inhibit SLC7A11, disrupt balance, massive ferroptosis, impaired vivo. Taken together, study reveals novel mechanism super-enhancer-driven positively meet alleviated demand cystine maintain highlighting feasibility promise targeting