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Dysregulation of mRNA methylation contributes to tumorigenesis and virus replication. However, the association of N\n                    <jats:sup>1<\/jats:sup>\n                    \u2010methyladenosine (m\n                    <jats:sup>1<\/jats:sup>\n                    A) modification with HCC progression and HBV replication remains unclear. Here, single\u2010nucleus RNA sequencing (snRNA\u2010seq) of 4 HCC and 7 adjacent tissues (2 from this study and 5 from the GSE242889) revealed elevated mRNA methylation in HCCs, with increased expression of m\n                    <jats:sup>1<\/jats:sup>\n                    A \u201cwriters\u201d and \u201creaders\u201d and decreased expression of m\n                    <jats:sup>1<\/jats:sup>\n                    A \u201cerasers\u201d. Among them, m\n                    <jats:sup>1<\/jats:sup>\n                    A writer\n                    <jats:italic>TRMT6<\/jats:italic>\n                    was up\u2010regulated in HCC and correlated with poor patient prognosis. TRMT6 knockdown strikingly restrained the malignant phenotypes and tumorigenicity of HCC cells as well as HBV replication. Mechanistically, TRMT6\u2010mediated m\n                    <jats:sup>1<\/jats:sup>\n                    A modification enhanced the stability and translation efficiency of cyclin\u2010dependent kinase 9 (\n                    <jats:italic>CDK9<\/jats:italic>\n                    ) mRNA. Elevated CDK9 facilitated HCC progression by up\u2010regulating its downstream oncogenic effectors, and stimulated HBV replication via TARDBP phosphorylation at Ser254 to enhance pgRNA transcription and repress pgRNA splicing. CDK9 inhibitor FIT\u2010039 abrogated these effects without obvious toxicity. Thus, TRMT6\u2010mediated m\n                    <jats:sup>1<\/jats:sup>\n                    A modification dually drives HCC malignancy and HBV replication, representing a promising therapeutic target, and CDK9 inhibition may constitute an effective strategy for HBV\u2010related HCC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514172","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:44:48Z","timestamp":1776681888000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRMT6\u2010Mediated m\n                    <sup>1<\/sup>\n                    A Modification of\n                    <i>CDK9<\/i>\n                    mRNA is a Dual\u2010Pronged Pathogenic Driver for HBV\u2010Related Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Rui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"Department of Infectious Diseases Tangdu Hospital The Fourth Military Medical University  Xi'an P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zong","sequence":"additional","affiliation":[{"name":"Yulin Hospital The First Affiliated Hospital of Xi'an Jiaotong University  Yulin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radio\u2010Oncology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"International Joint Research Center for Tumor Precision Medicine of Shaanxi Province The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daxu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Stomatology The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siwen","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism The Second Affiliated Hospital Xi'an Jiaotong University  Xi'an P. R. 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