A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD⁺/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.

饮食中果糖摄入量的显着增加被认为是癌症的潜在驱动因素。癌细胞利用果糖的代谢适应为其恶性生长提供了优势，但尚未确定引人注目的治疗靶点。在这里，我们表明可以通过靶向从头丝氨酸合成途径 (SSP)来抑制白血病细胞的果糖代谢。与正常细胞不同，白血病细胞与富含葡萄糖的条件相比，在富含果糖的条件下变得显着依赖 SSP。这种代谢程序由氧化还原辅因子 NAD ⁺的比例介导/NADH，增加的 SSP 通量有利于从谷氨酰胺生成 α-酮戊二酸，这使得白血病细胞即使在没有葡萄糖的情况下也能增殖。PHGDH 是 SSP 中的一种限速酶，在高果糖存在的情况下，抑制 PHGDH 可显着减少小鼠的白血病移植，证实了 SSP 在白血病细胞代谢可塑性中的重要作用。