真核生物核糖体对于癌细胞的生存至关重要。干扰核糖体生物合成会引起核仁应激或核糖体应激，从而限制癌细胞生长，因为快速增殖的癌细胞需要更活跃的核糖体生物合成。在这项研究中，我们发现UTP11通过结合前rRNA处理因子MPP10在18S核糖体RNA（rRNA）的生物合成中发挥重要作用。UTP11在人类癌症中过度表达并与不良预后相关。有趣的是，UTP11的耗竭通过p53依赖和独立机制抑制了体内外的癌细胞生长，而UTP11的过表达则促进了癌细胞生长和进展。一方面，UTP11的削减阻碍18S rRNA的生物合成以触发核仁应激，从而通过核糖体蛋白RPL5和RPL11阻止MDM2介导的p53泛素化和降解。另一方面，UTP11的缺陷通过促进NRF2 mRNA降解来抑制SLC7A11的表达，导致谷胱甘肽（GSH）水平降低和铁死亡增强。总之，我们的研究揭示了UTP11在维持癌细胞生存和生长中的关键作用，因为UTP11的耗竭导致p53依赖的癌细胞生长停滞和p53独立的铁死亡。版权所有©2023作者。由Elsevier B.V.出版，未经许可，禁止一切形式的转载和传播。

The eukaryotic ribosome is essential for cancer cell survival. Perturbation of ribosome biogenesis induces nucleolar stress or ribosomal stress, which restrains cancer growth, as rapidly proliferating cancer cells need more active ribosome biogenesis. In this study, we found that UTP11 plays an important role in the biosynthesis of 18S ribosomal RNAs (rRNA) by binding to the pre-rRNA processing factor, MPP10. UTP11 is overexpressed in human cancers and associated with poor prognoses. Interestingly, depletion of UTP11 inhibits cancer cell growth in vitro and in vivo through p53-depedednt and -independent mechanisms, whereas UTP11 overexpression promotes cancer cell growth and progression. On the one hand, the ablation of UTP11 impedes 18S rRNA biosynthesis to trigger nucleolar stress, thereby preventing MDM2-mediated p53 ubiquitination and degradation through ribosomal proteins, RPL5 and RPL11. On the other hand, UTP11 deficiency represses the expression of SLC7A11 by promoting the decay of NRF2 mRNA, resulting in reduced levels of glutathione (GSH) and enhanced ferroptosis. Altogether, our study uncovers a critical role for UTP11 in maintaining cancer cell survival and growth, as depleting UTP11 leads to p53-dependent cancer cell growth arrest and p53-independent ferroptosis.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.