{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T03:52:39Z","timestamp":1784865159233,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014007","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"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":["82172301"],"award-info":[{"award-number":["82172301"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271795, 81771702"],"award-info":[{"award-number":["82271795, 81771702"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Foundation Project of Guizhou Health Commission","award":["gzwkj2025-616"],"award-info":[{"award-number":["gzwkj2025-616"]}]},{"DOI":"10.13039\/501100013078","name":"Natural Science Research Project of Guizhou Province","doi-asserted-by":"publisher","award":["Talent Project of the Institute [2023]-43"],"award-info":[{"award-number":["Talent Project of the Institute [2023]-43"]}],"id":[{"id":"10.13039\/501100013078","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2024AFB726"],"award-info":[{"award-number":["2024AFB726"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Inhibiting the activation of hepatic stellate cells (HSCs) represents a key therapeutic strategy for alleviating liver fibrosis induced by schistosomiasis. Diverse cell populations secrete pro-inflammatory cytokines and chemokines, which induce HSC activation and thereby promote hepatic fibrosis progression. Tristetraprolin (TTP) exerts a pivotal role in the post-transcriptional regulation of pro-inflammatory cytokines by either accelerating mRNA degradation or suppressing translation, a regulatory mechanism closely associated with the pathogenesis of various hepatic disorders. However, the pathological roles of TTP in\n                    <jats:italic>Schistosoma japonicum<\/jats:italic>\n                    -induced liver fibrosis remain largely elusive. Here, we report that TTP is upregulated in the liver during\n                    <jats:italic>S. japonicum<\/jats:italic>\n                    -induced liver fibrosis, and its overexpression markedly ameliorates this fibrotic pathology\n                    <jats:italic>in vivo<\/jats:italic>\n                    . We further identify that TTP negatively regulates TGF-\u03b21 mRNA stability by promoting N6-methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) RNA methylation, thereby inhibiting HSC activation. Mechanistically, TTP enhances transcription of the WT1-associated protein (\n                    <jats:italic>WTAP<\/jats:italic>\n                    ) gene through its interaction with SMAD2\/3. Furthermore, treatment with an m\n                    <jats:sup>6<\/jats:sup>\n                    A RNA methylation inhibitor confirms that TTP-mediated protection against\n                    <jats:italic>S. japonicum<\/jats:italic>\n                    -induced liver fibrosis, an effect associated with increased m\u2076A RNA methylation\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Thus, our findings uncover a novel and critical role of TTP in exerting its anti-fibrotic function via the WTAP\/m\n                    <jats:sup>6<\/jats:sup>\n                    A epitranscriptomic machinery in the pathogenesis of\n                    <jats:italic>S. japonicum<\/jats:italic>\n                    -induced liver fibrosis. This finding provides a rationale for the therapeutic targeting of TTP-mediated m\n                    <jats:sup>6<\/jats:sup>\n                    A RNA methylation in\n                    <jats:italic>S. japonicum<\/jats:italic>\n                    -induced liver fibrosis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014007","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T17:50:16Z","timestamp":1778694616000},"page":"e1014007","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tristetraprolin attenuates schistosomiasis-induced liver fibrosis through m\u2076A-mediated regulation of TGF-\u03b21 mRNA stability"],"prefix":"10.1371","volume":"22","author":[{"given":"Xuejun","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangbo","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junnan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebing","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigao","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanxuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifen","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9927-5236","authenticated-orcid":true,"given":"Rui","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"issue":"12","key":"ppat.1014007.ref001","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1010064","article-title":"Schistosome immunomodulators","volume":"17","author":"S Acharya","year":"2021","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1014007.ref002","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Y Koyama","year":"2017","journal-title":"J Clin Invest"},{"issue":"4","key":"ppat.1014007.ref003","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1053\/j.gastro.2014.07.018","article-title":"Cell death and cell death responses in liver disease: mechanisms and clinical relevance","volume":"147","author":"T Luedde","year":"2014","journal-title":"Gastroenterology"},{"issue":"9541","key":"ppat.1014007.ref004","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/S0140-6736(06)69440-3","article-title":"Human schistosomiasis","volume":"368","author":"B Gryseels","year":"2006","journal-title":"Lancet"},{"issue":"2","key":"ppat.1014007.ref005","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.jhep.2023.03.038","article-title":"An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH","volume":"79","author":"F Tacke","year":"2023","journal-title":"J Hepatol"},{"issue":"8","key":"ppat.1014007.ref006","doi-asserted-by":"crossref","first-page":"100524","DOI":"10.1016\/j.jhepr.2022.100524","article-title":"Understanding the cellular interactome of non-alcoholic fatty liver disease","volume":"4","author":"SJ Wallace","year":"2022","journal-title":"JHEP Rep"},{"issue":"5","key":"ppat.1014007.ref007","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1002\/hep.31188","article-title":"Lipopolysaccharide reverses hepatic stellate cell activation through modulation of cMyb, small mothers against decapentaplegic, and CCAAT\/enhancer-binding protein C\/EBP transcription factors","volume":"72","author":"A Sharma","year":"2020","journal-title":"Hepatology"},{"key":"ppat.1014007.ref008","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.bbagrm.2013.02.003","article-title":"Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action.","volume":"1829","author":"SA Brooks","year":"2013","journal-title":"Biochim Biophys Acta"},{"issue":"2","key":"ppat.1014007.ref009","doi-asserted-by":"crossref","first-page":"71","DOI":"10.4251\/wjgo.v11.i2.71","article-title":"AU-rich element-binding proteins in colorectal cancer","volume":"11","author":"N Legrand","year":"2019","journal-title":"World J Gastrointest Oncol"},{"issue":"8","key":"ppat.1014007.ref010","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1080\/15548627.2019.1687985","article-title":"RNA-binding protein ZFP36\/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells","volume":"16","author":"Z Zhang","year":"2020","journal-title":"Autophagy"},{"issue":"2","key":"ppat.1014007.ref011","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.jcmgh.2020.09.012","article-title":"Tristetraprolin promotes hepatic inflammation and tumor initiation but restrains cancer progression to malignancy","volume":"11","author":"D Dolicka","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"5","key":"ppat.1014007.ref012","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/s41422-018-0034-6","article-title":"RNA N6-methyladenosine modification in cancers: current status and perspectives","volume":"28","author":"X Deng","year":"2018","journal-title":"Cell Res"},{"issue":"4","key":"ppat.1014007.ref013","article-title":"RNA m6A modification in liver biology and its implication in hepatic diseases and carcinogenesis","volume":"323","author":"W Ma","year":"2022","journal-title":"Am J Physiol Cell Physiol"},{"issue":"23","key":"ppat.1014007.ref014","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.149276","article-title":"TTP protects against acute liver failure by regulating CCL2 and CCL5 through m6A RNA methylation","volume":"6","author":"P Xiao","year":"2021","journal-title":"JCI Insight"},{"key":"ppat.1014007.ref015","first-page":"20","article-title":"Nuclear tristetraprolin acts as a corepressor of multiple steroid nuclear receptors in breast cancer cells","volume":"7","author":"T Barrios-Garc\u00eda","year":"2016","journal-title":"Mol Genet Metab Rep"},{"issue":"1","key":"ppat.1014007.ref016","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1073\/pnas.1715965115","article-title":"MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor","volume":"115","author":"X He","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"ppat.1014007.ref017","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1012153","article-title":"Sja-let-7 suppresses the development of liver fibrosis via Schistosoma japonicum extracellular vesicles","volume":"20","author":"H Zhong","year":"2024","journal-title":"PLoS Pathog"},{"issue":"7695","key":"ppat.1014007.ref018","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/nature25784","article-title":"The SMAD2\/3 interactome reveals that TGF\u03b2 controls m6A mRNA methylation in pluripotency","volume":"555","author":"A Bertero","year":"2018","journal-title":"Nature"},{"issue":"1","key":"ppat.1014007.ref019","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1038\/s41598-017-02422-8","article-title":"Characteristics of IL-9 induced by Schistosoma japonicum infection in C57BL\/6 mouse liver","volume":"7","author":"L Li","year":"2017","journal-title":"Sci Rep"},{"key":"ppat.1014007.ref020","article-title":"Screening of ferroptosis-related genes in sepsis-induced liver failure and analysis of immune correlation","volume":"10","author":"Q Chen","year":"2022","journal-title":"PeerJ"},{"key":"ppat.1014007.ref021","doi-asserted-by":"crossref","first-page":"798551","DOI":"10.3389\/fcell.2022.798551","article-title":"Integrative analysis of RNA expression and regulatory networks in mice liver infected by Echinococcus multilocularis","volume":"10","author":"T Liu","year":"2022","journal-title":"Front Cell Dev Biol"},{"issue":"2","key":"ppat.1014007.ref022","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1096\/fj.201800098RR","article-title":"linc-SCRG1 accelerates liver fibrosis by decreasing RNA-binding protein tristetraprolin","volume":"33","author":"J-C Wu","year":"2019","journal-title":"FASEB J"},{"issue":"5","key":"ppat.1014007.ref023","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1042\/BST20160166","article-title":"The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases","volume":"44","author":"AR Clark","year":"2016","journal-title":"Biochem Soc Trans"},{"issue":"4","key":"ppat.1014007.ref024","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1007\/s11033-012-2302-8","article-title":"Transcriptional regulation of tristetraprolin by NF-\u03baB signaling in LPS-stimulated macrophages","volume":"40","author":"Y-L Chen","year":"2013","journal-title":"Mol Biol Rep"},{"issue":"2","key":"ppat.1014007.ref025","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1080\/01480545.2022.2028822","article-title":"Salvianolic acid A suppresses CCl4-induced liver fibrosis through regulating the Nrf2\/HO-1, NF-\u03baB\/I\u03baB\u03b1, p38 MAPK, and JAK1\/STAT3 signaling pathways","volume":"46","author":"S Li","year":"2023","journal-title":"Drug Chem Toxicol"},{"issue":"1","key":"ppat.1014007.ref026","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1074\/jbc.M113.466326","article-title":"Mutational and structural analysis of the tandem zinc finger domain of tristetraprolin","volume":"289","author":"WS Lai","year":"2014","journal-title":"J Biol Chem"},{"issue":"34","key":"ppat.1014007.ref027","doi-asserted-by":"crossref","first-page":"29848","DOI":"10.1074\/jbc.M110.217745","article-title":"Cell type-specific target selection by combinatorial binding of Smad2\/3 proteins and hepatocyte nuclear factor 4alpha in HepG2 cells","volume":"286","author":"A Mizutani","year":"2011","journal-title":"J Biol Chem"},{"issue":"8","key":"ppat.1014007.ref028","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/j.1440-1681.2011.05592.x","article-title":"Cell biology of Smad2\/3 linker region phosphorylation in vascular smooth muscle","volume":"39","author":"HB Rezaei","year":"2012","journal-title":"Clin Exp Pharmacol Physiol"},{"issue":"1","key":"ppat.1014007.ref029","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jhep.2020.02.005","article-title":"Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12","volume":"73","author":"JP Arab","year":"2020","journal-title":"J Hepatol"},{"issue":"2","key":"ppat.1014007.ref030","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"R Bataller","year":"2005","journal-title":"J Clin Invest"},{"issue":"6","key":"ppat.1014007.ref031","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1002\/hep.510260618","article-title":"Hepatic expression of c-Myb in chronic human liver disease","volume":"26","author":"T Kitada","year":"1997","journal-title":"Hepatology"},{"issue":"4","key":"ppat.1014007.ref032","article-title":"RNA m6A modification in liver biology and its implication in hepatic diseases and carcinogenesis","volume":"323","author":"W Ma","year":"2022","journal-title":"Am J Physiol Cell Physiol"},{"issue":"1","key":"ppat.1014007.ref033","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12943-020-01172-y","article-title":"The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis","volume":"19","author":"M Chen","year":"2020","journal-title":"Mol Cancer"},{"issue":"3","key":"ppat.1014007.ref034","doi-asserted-by":"crossref","first-page":"4120","DOI":"10.1096\/fj.201902438R","article-title":"Upregulation of KSRP by miR-27b attenuates schistosomiasis-induced hepatic fibrosis by targeting TGF-\u03b21","volume":"34","author":"S Wang","year":"2020","journal-title":"FASEB J"},{"issue":"6","key":"ppat.1014007.ref035","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.cell.2019.07.021","article-title":"LECT2, a ligand for Tie1, plays a crucial role in liver fibrogenesis","volume":"178","author":"M Xu","year":"2019","journal-title":"Cell"},{"issue":"15","key":"ppat.1014007.ref036","first-page":"7418","article-title":"The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation","volume":"44","author":"C Tiedje","year":"2016","journal-title":"Nucleic Acids Res"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1014007","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:53:33Z","timestamp":1779299613000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014007"}},"subtitle":[],"editor":[{"given":"David L.","family":"Williams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":36,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1014007","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]}}}