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However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C\u2010C motif chemokine receptor 9 (CCR9) was highly expressed in HBV\u2010related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg\u2010positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV\u2010HBV mouse model both exhibited a significant elevation in global N6\u2010methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429\u2010mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429\u2010mediated\u00a0m6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV\u2010related HCC.<\/jats:p>","DOI":"10.1002\/jmv.29894","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T07:14:26Z","timestamp":1724915666000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Small HBV surface antigen\u00a0drives regorafenib resistance in HCC via KIAA1429\u2010dependent m6A modification of CCR9"],"prefix":"10.1002","volume":"96","author":[{"given":"Zhao","family":"Lv","sequence":"first","affiliation":[{"name":"State Key Laboratory of Virology, Department of Medical Microbiology School of Basic Medical Sciences, Wuhan University Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijuan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, 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