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Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG <jats:italic>N<\/jats:italic>\u2010glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG<jats:sub>1<\/jats:sub> <jats:italic>N<\/jats:italic>\u2010glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG<jats:sub>1<\/jats:sub> with agalactosyl <jats:italic>N<\/jats:italic>\u2010glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (Fc\u03b3R) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of Fc\u03b3RIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast\u2010like morphology, enhanced migration and invasion capabilities, and enhanced expression of the Fc\u03b3RIIIa downstream tyrosine\u2010protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)\u2010\u03b21, total collagen, platelet\u2010derived growth factor subunit B and its receptors, pro\u2010collagen I\u2010\u03b11, \u03b1\u2010smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed <jats:italic>FCGR3A<\/jats:italic> and were reduced in <jats:italic>FCGR3A<\/jats:italic> knockout cells. Agalactosyl IgG and TGF\u2010\u03b21 each increased <jats:italic>FCGR3A<\/jats:italic> in HSCs. Furthermore, serum TGF\u2010\u03b21 concentrations in patients were positively correlated with agalactosyl IgG<jats:sub>1<\/jats:sub> levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC\u2010Fc\u03b3RIIIa, and TGF\u2010\u03b21. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through Fc\u03b3RIIIa. \u00a9 2024 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6303","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:09:04Z","timestamp":1718669344000},"page":"508-519","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Agalactosyl <scp>IgG<\/scp> induces liver fibrogenesis via <scp>Fc<\/scp> gamma receptor 3a on human hepatic stellate cells"],"prefix":"10.1002","volume":"263","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4451-2887","authenticated-orcid":false,"given":"Cheng\u2010Hsun","family":"Ho","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Science, College of Medical Science and Technology I\u2010Shou University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting\u2010Tsung","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien\u2010Chang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, College of Health Sciences Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4183-3872","authenticated-orcid":false,"given":"Sheng\u2010Fan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, College of Health Sciences Kaohsiung Medical University  Kaohsiung Taiwan"},{"name":"Center for Tropical Medicine and Infectious Disease Research Kaohsiung Medical University  Kaohsiung Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(16)30081-4"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-00372-7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24282"},{"key":"e_1_2_8_5_1","first-page":"874","article-title":"JAMA patient page. 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