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However, the mechanism by which this variant leads to liver fibrosis has not been unveiled yet. Using induced pluripotent stem cell (iPSC)\u2010derived hepatic stellate cells (iHSC) containing a single nucleotide polymorphism (SNP) within PNPLA3, this study sought to clarify the mechanism through which this PNPLA3 SNP induces liver fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Two types of iPSC (PNPLA3rs73840989(C):Wild, PNPLA3rs73840989(G):Variant) were differentiated into iHSC. iHSC were activated by TGF\u2010\u03b21.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TGF\u2010\u03b21 stimulation resulted in significantly higher secretion of the liver fibrosis markers \u03b1SMA and COL1A1 in Variant\u2010iHSCs than in Wild\u2010iHSCs. Variant\u2010iHSC secreted significantly more PDGF and TGF\u2010\u03b2 and had significantly higher cell proliferative and migration ability. RNA sequencing showed that gene expression related to collagen\u2010containing extracellular matrix and collagen metabolic processes was elevated in Variant\u2010iHSC. We focused on AMIGO2 expression because Variant\u2010iHSC expressed significantly more AMIGO2 than Wild\u2010iHSC. AMIGO2 knockdown using siRNA in Variant\u2010iHSC significantly reduced migration and proliferation ability. Additionally, significant changes were observed in Vimentin and E\u2010cadherin, along with decreases in EMT activity and protein expression of \u03b1SMA and COL1A1. Staining for AMIGO2 in cirrhotic and normal liver samples showed that AMIGO2 protein expression was observed in PNPLA3\u2010variant samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PNPLA3 SNP\u2010induced liver fibrosis involves EMT of HSC via AMIGO2 expression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70770","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:36:27Z","timestamp":1783056987000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>PNPLA3 I148M<\/scp>\n                    Variant Activates Hepatic Stellate Cells via\n                    <scp>AMIGO2<\/scp>\n                    Upregulation Using\n                    <scp>iPSC<\/scp>\n                    \u2010Derived Model"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4158-3287","authenticated-orcid":false,"given":"Katsuya","family":"Toshida","sequence":"first","affiliation":[{"name":"Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Takeishi","sequence":"additional","affiliation":[{"name":"Department of Surgery and Science, Graduate School of Medical Sciences Kyushu University  Fukuoka Japan"},{"name":"Department of Hepato\u2010Biliary\u2010Pancreatic Surgery Clinical Research Institute, National Hospital Organization Kyushu Medical Center  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0382-2520","authenticated-orcid":false,"given":"Shinji","family":"Itoh","sequence":"additional","affiliation":[{"name":"Department of Surgery and Science, Graduate School of 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