{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:54:46Z","timestamp":1787496886287,"version":"build-2736575974"},"reference-count":30,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T00:00:00Z","timestamp":1661731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cholangiocyte death accompanied by the progression of primary biliary cholangitis (PBC) has not yet been thoroughly investigated. Thus, we are aimed to explore the role of HSP90 and a potential treatment strategy in cholangiocyte necroptosis. First, we detected the expression of HSP90 and necroptotic markers in liver tissues from patients and mice with PBC by immunohistochemistry (IHC) and real\u2010time polymerase chain reaction\u00a0(PCR). Then, the HSP90 inhibitor, 17\u2010dimethylaminoethylamino\u201017\u2010demethoxygeldanamycin\u00a0(17\u2010DMAG), was administered by intraperitoneal injection to evaluate its therapeutic effect for PBC by IHC, real\u2010time\u00a0PCR, and western blotting. Human intrahepatic bile duct epithelial cells (HIBECs) were induced to necroptosis by toxic bile acid and lipopolysaccharide\u00a0(LPS) treatment, and evaluated via Cell Counting Kit\u20108 and flow cytometry assays. Additionally, 17\u2010DMAG, cycloheximide, and a proteasome inhibitor were used to evaluate the role of HSP90 in cholangiocyte necroptosis. We found that the expression of HSP90 was elevated in the cholangiocytes of patients and mice with PBC, along with higher expressions of receptor\u2010interacting serine\/threonine\u2010protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain\u2010like protein (MLKL), and\u00a0phosphorylated\u2010MLKL\u00a0(p\u2010MLKL). Proinflammatory cytokines and antibody levels of the E2 subunit of pyruvate dehydrogenase complex decreased after treatment with 17\u2010DMAG in PBC mice. Meanwhile, RIPK1, RIPK3, phosphorylated\u2010RIPK3, MLKL, and p\u2010MLKL protein expressions decreased with 17\u2010DMAG treatment. In vitro, 17\u2010DMAG and necrostatin\u20101 prevented glycochenodeoxycholic acid and LPS\u2010induced necroptosis of HIBECs. Immunoprecipitation and high\u2010performance liquid chromatography\u2013mass spectrometry analysis showed that RIPK1 combined with HSP90. Additionally, the 17\u2010DMAG treatment reduced the RIPK1 half\u2010life. Overall, 17\u2010DMAG might be a potential therapeutic agent for PBC via cholangiocyte necroptosis prevention by accelerating RIPK1 degradation.<\/jats:p>","DOI":"10.1002\/jcb.30321","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T14:55:07Z","timestamp":1661784907000},"page":"1857-1872","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The HSP90 inhibitor 17\u2010DMAG alleviates primary biliary cholangitis via cholangiocyte necroptosis prevention"],"prefix":"10.1002","volume":"123","author":[{"given":"Liuying","family":"Chen","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqian","family":"Fan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"},{"name":"Department of Gastroenterology General Hospital of the Yangtze River Shipping Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huikuan","family":"Chu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Du","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiong","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan 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