ENO1 promotes acute myeloid leukemia progression through SCD1-mediated lipid metabolism reprogramming.

α-Enolase (ENO1) is a potential therapeutic target in acute myeloid leukemia (AML), owing to its elevated expression in AML cells. In this study, we investigated the association between high ENO1 expression, accelerated tumor progression, and poor AML prognosis. Transcriptomic and metabolomic analyses indicated that ENO1 directly modulates lipid metabolism via regulating stearoyl-coenzyme A desaturase 1 (SCD1) expression. We further demonstrated that ENO1 functions as a DNA-binding protein, interacting with the SCD1 promoter region to enhance SCD1 transcription. This results in increased synthesis of monounsaturated fatty acids, leading to increased resistance to lipid peroxidation and ferroptosis. Based on these results, we found that SSI-4, an SCD1 inhibitor, could enhance chemosensitivity of daunorubicin (DNR), which can induce ferroptosis in tumor cells, effectively reducing the resistance to ferroptosis in AML cells exhibiting high ENO1 expression. Overall, our study elucidates the mechanism of ENO1 that promotes SCD1 transcription, driving lipid reprogramming and ferroptosis resistance within AML. In addition, it highlights the therapeutic potential of combining SCD1 inhibition with DNR for patients with AML with elevated ENO1 expression levels.