Ouabain-mediated IGF2BP2–GLS/NOS3 axis affects arginine metabolism in diffuse large B-cell lymphoma

Our group has previously demonstrated that ouabain can contribute to the malignant progression of diffuse large B-cell lymphoma (DLBCL) by regulating insulin-like growth factor 2 mRNA binding protein (IGF2BP2) at the genetic level. However, its potential impact on DLBCL metabolism remains unclear. To investigate this, we introduced ouabain or IGF2BP2 knockdown into DLBCL cells and observed that both treatments influenced the arginine metabolic pathway, as revealed by non-targeted metabolomics analysis. We further found significant changes in two genes: nitric oxide synthase 3 (NOS3) and glutaminase (GLS), which were involved in arginine metabolism. And it confirmed that NOS3 and GLS are highly expressed in DLBCL and associated with shorter patient survival. Real-time quantitative PCR (RT-qPCR) indicated that the expression levels of NOS3 and GLS were regulated by IGF2BP2. Cell proliferation was inhibited after interference with GLS and NOS3. Cell cycle and apoptosis experiments revealed that interference with GLS and NOS3 can delay cell progression and promote cell apoptosis. In conclusion, our study reveals that ouabain can interfere with arginine metabolism via the IGF2BP2-GLS/NOS3 axis, contributing to the progression of DLBCL. This provides novel targeted therapeutic strategies and potential targets for DLBCL treatment.