Targeting NAT10 Inhibits Hepatocarcinogenesis via ac4C-Mediated SMAD3 mRNA Stability

  • Exploration (Beijing). 2025 Sep 4;5(6):20250075. doi: 10.1002/EXP.20250075.
Yigan Zhang  1 ,  Yanbin Dong  2 ,  Shuwen Chen  1 ,  Hao Deng  3 ,  Weiru Yu  4 ,  Bonan Chen  5 ,  Minjie Chen  6 ,  Wanglong Liu  7 ,  Xiao Tan  3 ,  Jiaxin Ni  1 ,  Daniel Rigden  8 ,  Xuan Wang  8  9 ,  Wuhua Zhou  6 ,  Jia Meng  1  8  9 ,  Juan Chen  4 ,  Yuanchao Xue  1  10  7 ,  Zhongji Meng  1
Affiliations
  • 1. Institute of Biomedical Research Department of Infectious Diseases Regulatory Mechanism and Targeted Therapy for Liver Cancer, Shiyan Key Laboratory Hubei Provincial Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer Taihe Hospital (First Clinical College of Medicine) Hubei University of Medicine Shiyan Hubei China.
  • 2. Department of Pathology The Affiliated Lianyungang Hospital of Xuzhou Medical University The First People's Hospital of Lianyungang Lianyungang China.
  • 3. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy College of Basic Medical Science China Three Gorges University Yichang P. R. China.
  • 4. Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing China.
  • 5. Department of Anatomical and Cellular Pathology State Key Laboratory of Translational Oncology Sir Y. K. Pao Cancer Center Prince of Wales Hospital The Chinese University of Hong Kong Hong Kong China.
  • 6. Department of Hepatobiliary Pancreatic Surgery Affiliated Taihe Hospital Hubei University of Medicine Shiyan City Hubei Province China.
  • 7. School of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical University Wenzhou China.
  • 8. Department of Biochemistry Cell and Systems Biology Institute of Systems Molecular and Integrative Biology University of Liverpool Liverpool UK.
  • 9. Department of Biological Sciences School of Science Xi'an Jiaotong-Liverpool University Suzhou China.
  • 10. Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences Beijing China.
PMID: 41476650 DOI: 10.1002/EXP.20250075
Abstract

Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality, with limited effective treatment options. N-acetyltransferase 10 (NAT10) is the only known acetyltransferase for mRNA ac4C modification and is recognized as a biomarker for HCC, promoting its progression. However, the critical role of NAT10 in hepatocarcinogenesis remains to be fully elucidated, and the identification of suitable small-molecule inhibitors targeting NAT10 is of great interest. Here, we report that NAT10 promotes HCC progression by stabilizing Smad Family member 3 (SMAD3) mRNA through ac4C modification. Clinically, NAT10 is highly expressed in HCC tissues and is significantly associated with poor prognosis. Functionally, NAT10 downregulation inhibits HCC cell proliferation, invasion, and epithelial-mesenchymal transition, while promoting anoikis in vitro. Additionally, NAT10 depletion significantly impairs tumor growth, metastasis, and hepatocarcinogenesis in vivo. Mechanistically, NAT10 enhances oncogene SMAD3 mRNA stability via ac4C modification, thereby activating TGF-β signaling pathway. We also identify a novel small-molecule inhibitor, NAT10-2023, which effectively blocks NAT10 activity. Notably, NAT10-2023 treatment significantly reduces intracellular RNA ac4C modification levels and disrupts NAT10-RNA interactions, leading to suppressed tumor progression. Overall, NAT10 drives HCC progression via SMAD3 mRNA stability regulation, and NAT10-2023 could be a promising therapeutic candidate for targeting NAT10 in Cancer treatment.

Keywords
RNA ac4C modification; liver cancer; targeted drug development.
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