转录调控是基因表达中的关键步骤之一，其失调与肿瘤发生密切相关。真核生物翻译起始因子3亚单位i（eIF3i）通过选择性调控基因翻译来促进肿瘤生长，但其潜在机制尚不清楚。本研究显示，eIF3i在结直肠癌（CRC）中显著增加，并增强CRC细胞的增殖能力。通过Ribo-seq和蛋白质组学分析，我们鉴定了eIF3i在翻译水平上调控的几个基因，包括D-3磷酸甘油酸脱氢酶（PHGDH），这是脱新合饮酸途径中的速率限制性酶，参与代谢重编程的调控。PHGDH敲除显著抑制CRC细胞的增殖能力，并部分减弱eIF3i过表达引起的过度增长。机制上，METTL3介导的PHGDH mRNA上的m6A修饰促进其与eIF3i结合，最终导致更高的翻译速率。此外，eIF3i和PHGDH的敲除也能阻碍肿瘤在体内的生长。总体而言，本研究不仅揭示了PHGDH翻译的新调控机制，还证明了eIF3i是人类肿瘤中的重要代谢调控因子。版权所有© 2023年作者。由Elsevier公司出版，版权所有。

Translational regulation is one of the decisive steps in gene expression, and its dysregulation is closely related to tumorigenesis. Eukaryotic translation initiation factor 3 subunit i (eIF3i) promotes tumor growth by selectively regulating gene translation, but the underlying mechanisms are largely unknown. Here, we show that eIF3i is significantly increased in colorectal cancer (CRC) and reinforces the proliferation of CRC cells. Using Ribo-seq and proteomics analysis, several genes regulated by eIF3i at the translation level were identified, including D-3-phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in the de novo serine synthesis pathway that participates in metabolic reprogramming of tumor cells. PHGDH knockdown significantly represses CRC cell proliferation and partially attenuates the excessive growth induced by eIF3i overexpression. Mechanistically, METTL3-mediated m6A modification on PHGDH mRNA promotes its binding with eIF3i, ultimately leading to a higher translational rate. In addition, knocking down eIF3i and PHGDH impedes tumor growth in vivo. Collectively, this study not only uncovered a novel regulatory mechanism for PHGDH translation, but also demonstrated that eIF3i is a critical metabolic regulator in human cancer.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.