Nynrin Sustains Leukemia Stem Cell Viability via TXNIP Destabilization to Maintain Redox Homeostasis and Confer Venetoclax Resistance [KG-1a RNA-Seq]

Acute myeloid leukemia (AML) is driven by chemotherapy-resistant leukemia stem cells (LSCs), which rely on precise regulation of reactive oxygen species (ROS) for survival. We identify NYNRIN as a novel post-transcriptional regulator of LSC redox homeostasis. NYNRIN is selectively overexpressed in ROS-low LSCs and correlates with poor clinical outcomes in AML patients. Genetic targeting of Nynrin in murine models impairs LSC self-renewal, reduces leukemic burden, and prolongs survival, while sparing normal hematopoietic stem and progenitor cells. Mechanistically, NYNRIN binds to TXNIP mRNA, promoting its degradation and maintaining redox balance. Loss of NYNRIN leads to TXNIP stabilization, oxidative stress, mitochondrial dysfunction, and LSC apoptosis, which can be rescued by TXNIP knockdown or ROS scavenging. Notably, Nynrin ablation synergizes with venetoclax to overcome resistance, enhancing LSC cytotoxicity in vitro and in vivo. These findings highlight the NYNRIN-TXNIP-ROS axis as crucial for LSC maintenance and suggest NYNRIN inhibition as a potential therapeutic strategy for relapsed AML.