Optineurin enhances the chemoresistance by activating mitophagy in acute myeloid leukemia with NPM1 mutation.

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutation is a common genetic subtype with unique pathological features. However, current therapies remain challenged by relapse and drug resistance, underscoring an urgent need for novel therapeutic strategies. In this study, we identified hyperactivated mitophagy as a critical metabolic vulnerability in NPM1-mutated AML through bioinformatics analysis and experimental validation. Mechanistically, augmented mitophagy was driven by high expression of the mitophagy receptor optineurin (OPTN), which was upregulated by cytoplasmic dislocation of CCCTC binding factor (CTCF) in cells harboring the NPM1 mutant. Functionally, OPTN-mediated mitophagy promoted leukemogenesis by maintaining mitochondrial homeostasis, thereby sustaining leukemia cell proliferation and conferring chemoresistance. Correspondingly, genetic inhibition of OPTN suppressed mitophagy, disrupted mitochondrial homeostasis, and sensitized cells to cytarabine (Ara-C), ultimately potentiating its antileukemic efficacy in a cell-derived xenograft (CDX) model. Collectively, these findings indicate that OPTN-mediated mitophagy is an oncogenic driver in NPM1-mutated AML and that, targeted inhibition of this process is a promising strategy for overcoming chemoresistance, particularly in combination with conventional chemotherapy.