R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m⁶A/PFKP/LDHB axis

R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N⁶-methyladenosine (m⁶A)/YTH N⁶-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (LDHB) (two critical glycolytic genes) expression and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells, but not in normal CD34⁺ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (AML) cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism. Qing et al. demonstrate that R-2HG, a metabolite produced by mutant IDH, significantly suppresses aerobic glycolysis in sensitive (IDH-wild-type) leukemia cells, but not in normal hematopoietic stem/progenitor cells. R-2HG exerts glycolytic inhibitory effects by targeting the FTO/m⁶A/YTHDF2 signaling to downregulate PFKP and LDHB expression, contributing to its overall anti-tumor activity.