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Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)\u2013sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2\u2013sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1\u2013S1P. These findings suggest that the SphK1\u2013S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury.<\/jats:p>","DOI":"10.4049\/jimmunol.2400088","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T13:33:44Z","timestamp":1728912824000},"page":"1499-1507","source":"Crossref","is-referenced-by-count":5,"title":["Hepatitis B Virus Increases SphK1\u2013S1P Synthesis by Promoting the Availability of the Transcription Factor USF1"],"prefix":"10.1093","volume":"213","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4420-2184","authenticated-orcid":false,"given":"Lu","family":"Zhang","sequence":"first","affiliation":[{"name":"Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]},{"name":"Department of Laboratory Medicine, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Hui","family":"Song","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Liu","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin-Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Central Laboratory, Shanghai Xuhui Central Hospital\/Zhongshan\u2013Xuhui Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruo-Ran","family":"Zhou","sequence":"additional","affiliation":[{"name":"Suzhou Medical College, Soochow University , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1447-7593","authenticated-orcid":false,"given":"Jun-Chi","family":"Xu","sequence":"additional","affiliation":[{"name":"Fifth People\u2019s Hospital of Suzhou , Suzhou ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"He","sequence":"additional","affiliation":[{"name":"Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, First Affiliated Hospital of Soochow University, Soochow University , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"You-Li","family":"Lu","sequence":"additional","affiliation":[{"name":"Central Laboratory, Shanghai Xuhui Central Hospital\/Zhongshan\u2013Xuhui Hospital, Fudan University , Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Juan","family":"Gan","sequence":"additional","affiliation":[{"name":"Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing-Sheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Biology and Medical Sciences, Soochow University , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing-Zhen","family":"Han","sequence":"additional","affiliation":[{"name":"Center of Clinical Laboratory and Translational Medicine, Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital , Suzhou, Jiangsu ,","place":["People\u2019s Republic of China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"key":"2025020609292026300_r1","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.3390\/v11111077","article-title":"HBV infection in HIV-driven immune suppression","volume":"11","author":"Sarmati","year":"2019","journal-title":"Viruses"},{"key":"2025020609292026300_r2","doi-asserted-by":"crossref","first-page":"e2415","DOI":"10.1002\/rmv.2415","article-title":"Sphingosine-1-phosphate related signalling pathways manipulating virus replication","volume":"33","author":"Zhang","year":"2023","journal-title":"Rev. Med. Virol."},{"key":"2025020609292026300_r3","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/aps.2015.38","article-title":"Hepatitis B virus X protein promotes human hepatoma cell growth via upregulation of transcription factor AP2\u03b1 and sphingosine kinase 1","volume":"36","author":"Lu","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"2025020609292026300_r4","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.jhep.2009.12.017","article-title":"The molecular basis of the failed immune response in chronic HBV: therapeutic implications","volume":"52","author":"Maini","year":"2010","journal-title":"J. Hepatol."},{"key":"2025020609292026300_r5","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.4049\/jimmunol.2300569","article-title":"Liver-restricted type I IFN signature precedes liver damage in chronic hepatitis B patients stopping antiviral therapy","volume":"212","author":"Chua","year":"2024","journal-title":"J. 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