{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:45:11Z","timestamp":1768405511061,"version":"3.49.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Clonorchis sinensis (C. sinensis)<\/jats:italic> infection induces severe hepatobiliary injuries, which can cause inflammation, periductal fibrosis, and even cholangiocarcinoma. Sphingolipid metabolic pathways responsible for the generation of sphingosine-1-phosphate (S1P) and its receptor S1P receptors (S1PRs) have been implicated in many liver-related diseases. However, the role of S1PRs in <jats:italic>C. sinensis<\/jats:italic>-mediated biliary epithelial cells (BECs) proliferation and hepatobiliary injury has not been elucidated. In the present study, we found that <jats:italic>C. sinensis<\/jats:italic> infection resulted in alteration of bioactive lipids and sphingolipid metabolic pathways in mice liver. Furthermore, S1PR2 was predominantly activated among these S1PRs in BECs both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Using JTE-013, a specific antagonist of S1PR2, we found that the hepatobiliary pathological injuries, inflammation, bile duct hyperplasia, and periductal fibrosis can be significantly inhibited in <jats:italic>C. sinensis<\/jats:italic>-infected mice. In addition, both <jats:italic>C. sinensis<\/jats:italic> excretory-secretory products (CsESPs)- and S1P-induced activation of AKT and ERK1\/2 were inhibited by JTE-013 in BECs. Therefore, the sphingolipid metabolism pathway and S1PR2 play an important role, and may serve as potential therapeutic targets in hepatobiliary injury caused by <jats:italic>C. sinensis<\/jats:italic>-infection.<\/jats:p>","DOI":"10.3389\/fcimb.2022.1011378","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T17:33:20Z","timestamp":1666200800000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Clonorchis sinensis infection induces hepatobiliary injury via disturbing sphingolipid metabolism and activating sphingosine 1-phosphate receptor 2"],"prefix":"10.3389","volume":"12","author":[{"given":"Ji-Xin","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Zhi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian-Qian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Ling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Hong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephane","family":"Koda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beibei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren-Xian","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-Hua","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kui-Yang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6354","DOI":"10.1111\/febs.12446","article-title":"Sphingosine-1-phosphate receptor 2","volume":"280","author":"Adada","year":"2013","journal-title":"FEBS J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/s41575-019-0125-y","article-title":"Cholangiocyte pathobiology","volume":"16","author":"Banales","year":"2019","journal-title":"Nat. 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