NYNRIN safeguards leukemia stem cells by sustaining thioredoxin activity to maintain redox homeostasis

Leukemia stem cells (LSCs) primarily rely on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, a metabolic feature that inevitably generates excessive reactive oxygen species (ROS). NYNRIN (NYN domain and retroviral integrase containing) is highly expressed in LSC-like cells and is associated with poor prognosis in patients with acute myeloid leukemia (AML). Genetic targeting of NYNRIN impairs LSC-like cell maintenance and in vivo leukemogenic capacity in MLL-AF9- and HOXA9/MEIS1-driven AML models, and compromises the in vivo pathogenicity of patient-derived LSC-like cells. Mechanistically, NYNRIN sustains thioredoxin (Trx) activity by functioning as an RNA-binding protein that directly binds and degrades TXNIP mRNA via its NYN domain. Loss of NYNRIN stabilizes TXNIP mRNA, leading to TXNIP accumulation, which disrupts Trx-mediated redox buffering, induces ROS overproduction and mitochondrial dysfunction, and triggers LSC apoptosis. Notably, NYNRIN inhibition potentiates venetoclax efficacy by compromising Trx-mediated ROS clearance, lowering the apoptotic threshold of LSCs. Collectively, our findings reveal a critical NYNRIN-TXNIP-Trx axis that safeguards LSCs by enabling efficient ROS clearance. In patients with acute myeloid leukaemia (AML), the presence of leukaemic stem cells (LSCs) promotes resistance to therapy and is associated with poor prognosis. Here, the authors demonstrate that NYNRIN protects LSCs from oxidative stress by maintaining thioredoxin activity, identifying NYNRIN as a potential therapeutic target in AML.