Beyond Paracaspase Inhibition: MI-2 Exerts a Novel Pro-apoptotic Function in AML by Disrupting Lipid Homeostasis

Acute Myeloid Leukemia (AML) is a highly aggressive hematologic malignancy with a significant rate of relapse, necessitating the urgent development of novel therapeutic strategies. Drug repurposing, the strategy of identifying new therapeutic uses for existing compounds, represents a promising pathway to accelerate clinical translation.This study focuses on MI-2, a compound initially identified as a potent and selective inhibitor of the paracaspase Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1 (MALT1), which has shown efficacy in certain lymphoid malignancies. However, the anti-leukemic efficacy and mechanism of action of MI-2 in AML, where functional MALT1 protease activity is typically absent, remained unclear.