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.

R-2-羟基戊二酸 (R-2HG) 是一种由突变异柠檬酸脱氢酶 (IDH) 产生的代谢物，最近据报道具有抗肿瘤活性。然而，它对癌症代谢的影响在很大程度上仍然难以捉摸。在这里，我们证明 R-2HG 有效减弱（R-2HG 敏感）白血病细胞中的有氧糖酵解，这是癌症代谢的标志。从机制上讲，R-2HG 消除脂肪量和肥胖相关蛋白 (FTO)/ N ^{6 -}甲基腺苷 (m ⁶ A)/YTH N ^{6 -}甲基腺苷 RNA 结合蛋白 2 (YTHDF2) 介导的磷酸果糖激酶血小板的转录后上调( PFKP ) 和乳酸脱氢酶 B ( LDHB )（两个关键的糖酵解基因）表达，从而抑制有氧糖酵解。 FTO 、 PFKP或LDHB的敲低可重现 R-2HG 在（R-2HG 敏感）白血病细胞中诱导的糖酵解抑制作用，但在正常 CD34 ⁺造血干/祖细胞中则不然，并抑制体内白血病发生；相反，它们的过度表达会逆转 R-2HG 诱导的效应。 R-2HG 还抑制人原代IDH野生型急性髓系白血病 (AML) 细胞中的糖酵解并下调FTO / PFKP / LDHB表达，证明了其临床相关性。总的来说，我们的研究揭示了之前未被认识到的 R-2HG 和 RNA 修饰对白血病有氧糖酵解的影响，突出了针对癌症表观转录组学和代谢的治疗潜力。