ATGL suppresses ferroptosis in acute myeloid leukemia cells by modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.

Metabolic reprogramming disrupts energy homeostasis and promotes tumor cell proliferation. In the present study, high expression of adipose triglyceride lipase (ATGL) in patients with acute myeloid leukemia (AML) predicted a poor clinical prognosis. Furthermore, the aberrant upregulation of ATGL was confirmed to promote the malignant progression of AML through gene ablation, overexpression, and pharmacological inhibition of ATGL, particularly in FLT3-ITD-mutated AML. RNA sequencing, lipid peroxidation, cellular iron, and ROS assays were performed to confirm the association of ATGL with ferroptosis. Mechanistically, ATGL is positively correlated with stearoyl-CoA decarboxylase 1 (SCD1) and promotes the malignant progression of AML by inhibiting ferroptosis through the CEBPα/SCD1 axis. We established gilteritinib-resistant MOLM-13 and MV4-11 cell lines and collected cells from patients with FLT3-ITD mutations to confirm that ATGL inhibitors increased the efficacy of gilteritinib. Consequently, we constructed an AML xenograft model using cells derived from patients with FLT3-ITD-mutated AML to confirm the efficacy of combining ATGL inhibitors with gilteritinib in vivo. This study provides novel therapeutic targets and monitoring indicators for AML, along with new treatment strategies for patients with FLT3-ITD-mutated AML and those with relapsed/refractory FLT3-ITD-mutated AML.