RNA epigenetic modifications have been implicated in cancer progression. However, the interplay between distinct RNA modifications and its role in cancer metabolism remain largely unexplored. Our study demonstrates that N-acetyltransferase 10 (NAT10) is notably upregulated in ovarian cancer (OC), correlating with poor patient prognosis. IGF2BP1 enhances the translation of NAT10 mRNA in an m⁶A-dependent manner in OC cells. NAT10 drives tumorigenesis by mediating N4-acetylcytidine (ac⁴C) modification of ACOT7 mRNA, thereby augmenting its stability and translation. This NAT10-ACOT7 axis modulates fatty acid metabolism in cancer cells and promotes tumor progression by suppressing ferroptosis. Additionally, our research identifies fludarabine as a small molecule inhibitor targeting NAT10, inhibits the ac⁴C modification and expression of ACOT7 mRNA. By using cell derived xenograft model and patient derived organoid model, we show that fludarabine effectively suppresses ovarian tumorigenesis. Overall, our study highlights the pivotal role of the NAT10-ACOT7 axis in the malignant cancer progression, underscoring the potential of targeting NAT10-mediated ac⁴C modification as a viable therapeutic strategy for this disease.

RNA 表观遗传修饰与癌症进展有关。然而，不同 RNA 修饰与其在癌症代谢中的作用之间的相互作用在很大程度上仍未得到探索。我们的研究表明，N-乙酰转移酶 10 （NAT10） 在卵巢癌 （OC） 中显着上调，与患者预后不良相关。IGF2BP1 在 OC 细胞中以 m⁶A 依赖性方式增强 NAT10 mRNA 的翻译。NAT10 通过介导 ACOT7 mRNA 的 N4-乙酰胞苷 （ac⁴C） 修饰来驱动肿瘤发生，从而增强其稳定性和翻译。该 NAT10-ACOT7 轴调节癌细胞中的脂肪酸代谢，并通过抑制铁死亡促进肿瘤进展。此外，我们的研究发现氟达拉滨是一种靶向 NAT10 的小分子抑制剂，抑制 ac⁴C 修饰和 ACOT7 mRNA 的表达。通过使用细胞来源的异种移植模型和患者来源的类器官模型，我们表明氟达拉滨有效抑制卵巢肿瘤发生。总体而言，我们的研究强调了 NAT10-ACOT7 轴在恶性癌症进展中的关键作用，强调了靶向 NAT10 介导的 ac⁴C 修饰作为该疾病的可行治疗策略的潜力。