BACKGROUND: Acute myeloid leukemia (AML) is a prevalent malignancy of the hematologic system. Despite advancements in therapeutic approaches, significant heterogeneity and therapeutic resistance pose substantial challenges to treatment. Tumors driven by core transcription factors through super-enhancers can establish core transcriptional regulatory circuits (CRCs) that modulate oncogene expression programs. Identifying CRC is crucial for understanding disease-related transcriptional regulation. This study sought to predict and establish a CRC model for AML, identify genes critical for AML survival and explore their regulatory mechanisms in AML progression. METHODS: The dbCoRC tool was used for predictive analysis of H3K27ac ChIP-seq data from 11 AML samples to construct and validate the CRC model in AML patients. To elucidate the functional role of the CRC member IRF1, we utilized short hairpin RNA (shRNA) to knock down IRF1 in AML cells. RNA-seq, CUT&Tag and lipidomics technologies were subsequently used to investigate the regulatory roles and downstream mechanisms of IRF1 in AML. RESULTS: This study established a core transcriptional regulatory circuit consisting of IRF1, ELF1, ETV6, RUNX2, and MEF2D, which formed an interconnected autoregulatory loop. Further investigations revealed up-regulated expression of IRF1 in AML patients, which was associated with poor prognosis. Inhibition of IRF1 expression resulted in decreased AML cell proliferation and induced apoptosis, indicating its essential role in the survival of AML cells. Additionally, this study revealed that IRF1 directly regulates the transcription of key genes such as FASN, SCD, and SREBF1 for lipid synthesis, thereby affecting lipid metabolism in AML cells. CONCLUSION: In summary, this study identified IRF1 as a novel core transcription factor involved in AML pathogenesis. IRF1 collaborates with ELF1, ETV6, RUNX2, and MEF2D to form a core transcriptional regulatory circuit that promotes AML progression. Furthermore, we demonstrated that IRF1 directly regulates the expression of key genes involved in lipid metabolism, influencing the synthesis of diverse lipid molecules crucial for AML survival.