Wang Chen, Liu Jiangwen, Chang Haosheng, Wu Yali, Chai Zhiwei, Jia Ping, Yuan Yueyue, Tan Ling
Department of Vascular Intervention, The Third Affiliated Hospital of Shihezi University, Shihezi, China.
Department of Hepatobilary Surgery, The Third Affiliated Hospital of Shihezi University, Shihezi, China.
J Biochem Mol Toxicol. 2025 Sep;39(9):e70496. doi: 10.1002/jbt.70496.
N-acetyltransferase 10 (NAT10) catalyzes N4-acetylcytidine (ac4C) modification of mRNA, yet its role in hepatocellular carcinoma (HCC) and ferroptosis remains elusive. A retrospective study with 100 HCC patients assessed NAT10 and SLC7A11 expression. Immunohistochemistry evaluated protein levels in HCC tissues. In vitro experiments using HCC cell lines explored NAT10's impact on proliferation, migration, invasion, and apoptosis. In vivo, nude mice with HCC xenografts underwent stable si-NAT10 transfection, monitoring tumor growth and metastasis. Ferrostatin-1 treatment investigated NAT10's role in ferroptosis. RNA immunoprecipitation and acRIP assays examined NAT10's influence on SLC7A11 mRNA stability. Elevated NAT10 expression correlated with poor outcomes and TACE therapy resistance in HCC. NAT10 silencing inhibited HCC cell functions, promoting apoptosis and ferroptosis in vitro; Ferrostatin-1 reversed these effects. In vivo models confirmed NAT10's significance in HCC progression, reducing tumor volume and weight with increased apoptosis. Ferrostatin-1 counteracted these effects, underlining ferroptosis in NAT10-driven tumorigenesis. NAT10 knockdown increased Fe accumulation and decreased SLC7A11 and GPX4 expression, indicating that NAT10 knockdown enhanced ferroptosis. Mechanistically, NAT10 stabilized SLC7A11 mRNA via ac4C acetylation, suppressing ferroptosis. This epigenetic modification emerged as a regulator of ferroptosis evasion in HCC. Overall, NAT10 promotes HCC progression by inhibiting ferroptosis through ac4C acetylation of SLC7A11 mRNA.
N-乙酰转移酶10（NAT10）催化mRNA的N4-乙酰胞苷（ac4C）修饰，但其在肝细胞癌（HCC）和铁死亡中的作用仍不清楚。一项对100例HCC患者的回顾性研究评估了NAT10和溶质载体家族7成员11（SLC7A11）的表达。免疫组织化学评估了HCC组织中的蛋白水平。使用HCC细胞系进行的体外实验探讨了NAT10对增殖、迁移、侵袭和凋亡的影响。在体内，对携带HCC异种移植瘤的裸鼠进行稳定的小干扰RNA（si）-NAT10转染，监测肿瘤生长和转移。铁死亡抑制剂-1（Ferrostatin-1）处理研究了NAT10在铁死亡中的作用。RNA免疫沉淀和acRIP分析检测了NAT10对SLC7A11 mRNA稳定性的影响。NAT10表达升高与HCC患者的不良预后和经动脉化疗栓塞（TACE）治疗耐药相关。NAT10沉默抑制了HCC细胞功能，在体外促进凋亡和铁死亡；Ferrostatin-1逆转了这些效应。体内模型证实了NAT10在HCC进展中的重要性，通过增加凋亡减少肿瘤体积和重量。Ferrostatin-1抵消了这些效应，强调了铁死亡在NAT10驱动的肿瘤发生中的作用。NAT10基因敲低增加铁蓄积并降低SLC7A11和谷胱甘肽过氧化物酶4（GPX4）表达，表明NAT10基因敲低增强了铁死亡。机制上，NAT10通过ac4C乙酰化使SLC7A11 mRNA稳定，抑制铁死亡。这种表观遗传修饰成为HCC中逃避铁死亡的调节因子。总体而言，NAT10通过对SLC7A11 mRNA进行ac4C乙酰化抑制铁死亡，从而促进HCC进展。
