FLI1 is a sequence-specific ETS transcription factor that recognizes the DNA sequence 5'-C[CA]GGAAGT-3' and functions as a positive regulator of transcription 123. In normal physiology, FLI1 serves as a negative regulator of collagen-1 synthesis in vascular tissue 4 and is expressed in endothelial cells across multiple organ systems 5. FLI1 is clinically significant primarily through its involvement in Ewing sarcoma, where it becomes fused with EWSR1 in approximately 85% of cases, creating an oncogenic EWSR1-FLI1 chimeric transcription factor 6. This fusion protein exhibits neomorphic effects, rewiring the transcriptome and epigenome by inducing de novo enhancers at GGAA microsatellites 67. The EWSR1-FLI1 fusion activates pericentromeric heterochromatin, leading to pathogenic RNA expression secreted in extracellular vesicles, which promotes DNA damage and proinflammatory responses 7. Additionally, EWSR1 interacts with CENP-A to maintain centromere identity, a function relevant to genomic stability 8. Beyond Ewing sarcoma, FLI1 also functions in other cancers; in nasopharyngeal carcinoma, FLI1 orchestrates kynurenine metabolism through the CBP/STAT1-IDO1 axis, promoting immunosuppression and CD8+ T cell exhaustion 9. These diverse roles establish FLI1 as both a critical developmental regulator and a potent oncogenic driver.