Serine metabolism plays a pivotal role in cancer, making it an appealing therapeutic target. Two recent studies published in Nature Metabolism and Science Translational Medicine uncovered novel players and therapeutic opportunities within this crucial metabolic pathway. Papalazarou and colleagues employed genetic tools coupled with metabolomics and high-throughput imaging to identify and characterize membrane transporters involved in serine uptake and mitochondrial import in colorectal cancer. Notably, they showed that dual inhibition of these transporters in combination with impaired serine biosynthesis reduced tumor growth in xenograft models. In a parallel study, Zhang and colleagues identified isocitrate dehydrogenase I (IDH1) as a novel regulator of serine biosynthesis in non-small cell lung cancer (NSCLC). Through extensive mechanistic studies, they demonstrated that IDH1 enhances the expression of the key enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) via a non-canonical function independent of its enzymatic activity. Strikingly, pharmacological disruption of this novel function of IDH1 not only diminished tumor growth but also enhanced the anticancer efficacy of dietary serine restriction in mouse models of lung cancer. Together, these studies advance our mechanistic understanding of how cancer cells fulfill their serine requirements and reveal innovative therapeutic avenues to deprive tumors of this vital nutrient.

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解码丝氨酸代谢：揭示不断发展的癌症治疗的新途径

丝氨酸代谢在癌症中发挥着关键作用，使其成为有吸引力的治疗靶点。最近发表在《自然代谢》和《科学转化医学》上的两项研究揭示了这一关键代谢途径中的新参与者和治疗机会。Papalazarou 及其同事利用遗传工具与代谢组学和高通量成像相结合来识别和表征结直肠癌中参与丝氨酸摄取和线粒体输入的膜转运蛋白。值得注意的是，他们表明，这些转运蛋白的双重抑制与丝氨酸生物合成受损相结合，可以减少异种移植模型中的肿瘤生长。在一项平行研究中，Zhang 及其同事发现异柠檬酸脱氢酶 I (IDH1) 是非小细胞肺癌 (NSCLC) 丝氨酸生物合成的新型调节剂。通过广泛的机制研究，他们证明 IDH1 通过独立于其酶活性的非规范功能增强关键酶磷酸甘油酸脱氢酶 (PHGDH) 和磷酸丝氨酸转氨酶 1 (PSAT1) 的表达。引人注目的是，在药理学上破坏 IDH1 的这种新功能不仅可以减少肿瘤生长，还可以增强肺癌小鼠模型中饮食丝氨酸限制的抗癌功效。这些研究共同推进了我们对癌细胞如何满足其丝氨酸需求的机制理解，并揭示了剥夺肿瘤这种重要营养素的创新治疗途径。