{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:14:57Z","timestamp":1786976097059,"version":"build-2736575974"},"reference-count":59,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ft\u0131rma Kurumu","doi-asserted-by":"publisher","award":["1001: 117Z858"],"award-info":[{"award-number":["1001: 117Z858"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ft\u0131rma Kurumu","doi-asserted-by":"publisher","award":["1002: 221Z357"],"award-info":[{"award-number":["1002: 221Z357"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:p>Hepatic fibrogenesis is characterized by the excessive accumulation of extracellular matrix proteins, ultimately predisposing to hepatocarcinogenesis. The lack of reliable models that faithfully recapitulate early stage fibrogenesis is one of the main limitations in identifying translationally relevant therapeutics. Here, we establish a model using CRISPR\/Cas9\u2010mediated TP53 knockout iPSC (endoderm)\u2010derived human hepatic organoids (eHEPOs) to mimic human liver fibrosis. Transcriptomic profiling of TP53KO\u2010eHEPOs revealed enrichment of pathways associated with inflammation, ECM remodeling, and fibrosis, with notable alterations in pivotal fibrotic regulators. We also find increased expression of myofibroblasts and fibrosis markers (PDGFRB, COL1A1, COL3A1, COL11A1) and early liver cancer markers (GPC3 and MUC1). Histological analysis confirmed advanced fibrotic hallmarks and exposure to an exogenous profibrotic environment (pf\u2010ME) further enhanced these fibrotic phenotypes. This model provides a valuable platform for exploring the role of key driver genes, such as TP53, in the initiation and progression of fibrosis, enabling the study of hepatic progenitor cell transformation across diverse microenvironmental contexts. As such, it holds the potential for advancing early stage drug discovery and the identification of novel therapeutic targets for the treatment of liver fibrosis.<\/jats:p>","DOI":"10.1002\/1878-0261.70119","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T13:42:42Z","timestamp":1760017362000},"page":"668-687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Modeling hepatic fibrosis in\n                    <scp>TP53<\/scp>\n                    knockout\n                    <scp>iPSC<\/scp>\n                    \u2010derived human liver organoids"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0359-7645","authenticated-orcid":false,"given":"Mustafa","family":"Karabicici","sequence":"first","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"},{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soheil","family":"Akbari","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ceyda","family":"Caliskan","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canan","family":"Celiker","sequence":"additional","affiliation":[{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozden","family":"Oz","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"},{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"},{"name":"Department of Pathology Izmir Bozyaka Education and Research Hospital, University of Health Sciences  Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leman","family":"Binokay","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"},{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6khan","family":"Karakulah","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"},{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3963-2294","authenticated-orcid":false,"given":"Serif","family":"Senturk","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"},{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7264-0574","authenticated-orcid":false,"given":"Esra","family":"Erdal","sequence":"additional","affiliation":[{"name":"Izmir Biomedicine and Genome Center (IBG) Dokuz Eylul University Health Campus  Izmir Turkey"},{"name":"Izmir International Biomedicine and Genome Institute (IBG\u2010Izmir) Dokuz Eylul University  Izmir Turkey"},{"name":"Department of Medical Biology and Genetics, Faculty of Medicine Dokuz Eylul University  Izmir Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2023.05.010"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-020-02939-4"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26410-9"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.08.007"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.046"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2233"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30288"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-025-03380-0"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2022.12.062"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13050935"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S247133"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.04.036"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2016.63"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14370"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.639779"},{"key":"e_1_2_11_17_1","first-page":"34","article-title":"Kindlin\u20102 regulates hepatic stellate cells activation and liver fibrogenesis","volume":"4","author":"Yu J","year":"2018","journal-title":"Cell Death Dis"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0193601"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1546-9"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz114"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00841-x"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20200219"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14415"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgq101"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/4601085a"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00412-018-0659-8"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0227751"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7163-3_14"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101809"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.01.094"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02432"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073274817744625"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i43.15955"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12030453"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6909"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.256164"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00863-4"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-319256"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14418"},{"issue":"5","key":"e_1_2_11_41_1","first-page":"223","article-title":"Hepatoblast\u2010like cells populate the adult p53 knockout mouse liver: evidence for a hyperproliferative maturation\u2010arrested stem cell compartment","volume":"12","author":"Dumble ML","year":"2001","journal-title":"Cell Growth Differ"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2017.0078"},{"key":"e_1_2_11_43_1","article-title":"Generation of liver organoids from human induced pluripotent stem cells as liver fibrosis and steatosis models","author":"Tsang HY","year":"2021","journal-title":"bioRxiv"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.05.007"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22988-2"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2001453"},{"issue":"4","key":"e_1_2_11_47_1","first-page":"401","article-title":"Migration of hepatic stellate cells in fibrotic microenvironment of diseased liver model","volume":"7","author":"Chang YZ","year":"2008","journal-title":"Hepatobiliary Pancreat Dis Int"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2003.50012"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-023-00627-0"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.08.021"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03596-w"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.05.003"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0747"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S229065"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000362"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1912146117"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2010.0352"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30899"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00831-y"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32802"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70119","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1878-0261.70119","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T10:18:00Z","timestamp":1773915480000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.70119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":59,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/1878-0261.70119"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.70119","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v3\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70119\/v1\/review3","asserted-by":"object"}]},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]},"assertion":[{"value":"2024-12-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}