Targeting NAT10 Inhibits Hepatocarcinogenesis via ac4C-Mediated SMAD3 mRNA Stability
Yigan Zhang1, Yanbin Dong2, Shuwen Chen1
1Institute 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.
Exploration (Beijing, China)
|January 1, 2026
Summary
N-acetyltransferase 10 (NAT10) promotes hepatocellular carcinoma (HCC) by stabilizing SMAD3 mRNA. A new inhibitor, NAT10-2023, effectively blocks NAT10, offering a potential therapeutic strategy for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) presents significant morbidity and mortality with few effective treatments.
- N-acetyltransferase 10 (NAT10) is a key enzyme in mRNA ac4C modification and a biomarker for HCC progression.
- The precise role of NAT10 in hepatocarcinogenesis and targeted inhibitors require further investigation.
Purpose of the Study:
- To elucidate the critical role of NAT10 in hepatocarcinogenesis.
- To identify small-molecule inhibitors targeting NAT10 for HCC treatment.
- To investigate the mechanism by which NAT10 promotes HCC progression.
Main Methods:
- Analysis of NAT10 expression in HCC tissues and correlation with prognosis.
- In vitro and in vivo functional studies involving NAT10 downregulation.
- Mechanistic studies on NAT10-mediated mRNA stabilization and signaling pathway activation.
- Identification and evaluation of a novel small-molecule inhibitor, NAT10-2023.
Main Results:
- High NAT10 expression in HCC tissues is linked to poor prognosis.
- NAT10 downregulation inhibits HCC cell proliferation, invasion, EMT, and promotes anoikis in vitro.
- NAT10 depletion impairs tumor growth, metastasis, and hepatocarcinogenesis in vivo.
- NAT10 stabilizes SMAD3 mRNA via ac4C modification, activating the TGF-β pathway.
- NAT10-2023 effectively inhibits NAT10 activity, reduces RNA ac4C modification, and suppresses tumor progression.
Conclusions:
- NAT10 drives HCC progression by regulating SMAD3 mRNA stability through ac4C modification.
- NAT10 inhibition represents a promising therapeutic strategy for HCC.
- NAT10-2023 demonstrates potential as a novel therapeutic candidate for targeting NAT10 in cancer treatment.
