{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:47:47Z","timestamp":1791557267204,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["8240116292"],"award-info":[{"award-number":["8240116292"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005236","name":"Chinese Universities Scientific Fund","doi-asserted-by":"publisher","award":["2024TC056"],"award-info":[{"award-number":["2024TC056"]}],"id":[{"id":"10.13039\/501100005236","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Exploration"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality, with limited effective treatment options.\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetyltransferase 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\u2010molecule 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\u2010mesenchymal 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\u2010\u03b2 signaling pathway. We also identify a novel small\u2010molecule inhibitor, NAT10\u20102023, which effectively blocks NAT10 activity. Notably, NAT10\u20102023 treatment significantly reduces intracellular RNA ac4C modification levels and disrupts NAT10\u2010RNA interactions, leading to suppressed tumor progression. Overall, NAT10 drives HCC progression via SMAD3 mRNA stability regulation, and NAT10\u20102023 could be a promising therapeutic candidate for targeting NAT10 in cancer treatment.\n                  <\/jats:p>","DOI":"10.1002\/exp.20250075","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T07:56:33Z","timestamp":1756972593000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Targeting NAT10 Inhibits Hepatocarcinogenesis via ac4C\u2010Mediated SMAD3 mRNA Stability"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5435-1292","authenticated-orcid":false,"given":"Yigan","family":"Zhang","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbin","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pathology The Affiliated Lianyungang Hospital of Xuzhou Medical University The First People's Hospital of Lianyungang  Lianyungang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Deng","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy College of Basic Medical Science China Three Gorges University  Yichang P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiru","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonan","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Surgery Affiliated Taihe Hospital Hubei University of Medicine  Shiyan City Hubei Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanglong","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Tan","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy College of Basic Medical Science China Three Gorges University  Yichang P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Ni","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rigden","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Cell and Systems Biology Institute of Systems Molecular and Integrative Biology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Cell and Systems Biology Institute of Systems Molecular and Integrative Biology University of Liverpool  Liverpool UK"},{"name":"Department of Biological Sciences School of Science Xi\u2019an Jiaotong\u2010Liverpool University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuhua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Surgery Affiliated Taihe Hospital Hubei University of Medicine  Shiyan City Hubei Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Meng","sequence":"additional","affiliation":[{"name":"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"},{"name":"Department of Biochemistry Cell and Systems Biology Institute of Systems Molecular and Integrative Biology University of Liverpool  Liverpool UK"},{"name":"Department of Biological Sciences School of Science Xi\u2019an Jiaotong\u2010Liverpool University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9792-7995","authenticated-orcid":false,"given":"Juan","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchao","family":"Xue","sequence":"additional","affiliation":[{"name":"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"},{"name":"Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences Beijing China"},{"name":"School of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical University  Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongji","family":"Meng","sequence":"additional","affiliation":[{"name":"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 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