Aberrant RNA modifications lead to dysregulated gene expression and cancer progression. Ribosomal RNA (rRNA) accounts for more than 80% of a cell’s total RNA, but the functions and molecular mechanisms underlying rRNA modifications in cancers are poorly understood. Here, we show that the 18S rRNA N⁶-methyladenosine (m⁶A) methyltransferase complex METTL5–TRMT112 is upregulated in various cancer types and correlated with poor prognosis. In addition, we demonstrate the critical functions of METTL5 in promoting hepatocellular carcinoma (HCC) tumorigenesis in vitro and in mouse models. Mechanistically, depletion of METTL5-mediated 18S rRNA m⁶A modification results in impaired 80S ribosome assembly and decreased translation of mRNAs involved in fatty acid metabolism. We further reveal that ACSL4 mediates the function of METTL5 on fatty acid metabolism and HCC progression, and targeting ACSL4 and METTL5 synergistically inhibits HCC tumorigenesis in vivo. Our study uncovers mechanistic insights underlying mRNA translation control and HCC tumorigenesis through lipid metabolism remodeling and provides a molecular basis for the development of therapeutic strategies for HCC treatment.

异常的 RNA 修饰导致基因表达失调和癌症进展。核糖体 RNA (rRNA) 占细胞总 RNA 的 80% 以上，但人们对癌症中 rRNA 修饰的功能和分子机制知之甚少。在这里，我们显示 18S rRNA N ⁶ -甲基腺苷(m ⁶ A) 甲基转移酶复合物 METTL5-TRMT112 在各种癌症类型中上调，并与不良预后相关。此外，我们在体外和小鼠模型中证明了 METTL5 在促进肝细胞癌 (HCC) 肿瘤发生中的关键功能。机械地，METTL5 介导的 18S rRNA m ^6的消耗修改导致 80S 核糖体组装受损和参与脂肪酸代谢的 mRNA 翻译减少。我们进一步揭示 ACSL4 介导 METTL5 对脂肪酸代谢和 HCC 进展的功能，靶向 ACSL4 和 METTL5 在体内协同抑制 HCC 肿瘤发生。我们的研究通过脂质代谢重塑揭示了 mRNA 翻译控制和 HCC 肿瘤发生的机制见解，并为开发 HCC 治疗策略提供了分子基础。