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However, in vitro recapitulation of zone\u2010specific diversity, particularly in human pluripotent stem cell (PSC)\u2010derived hepatocyte\u2010like cells (HLCs), remains challenging, as these cells typically exhibit an immature phenotype. Here, we report a scalable differentiation protocol for generating 3D organoids from PSCs with defined zone 1 (z1\u2010HLCs) or zone 3 (z3\u2010HLCs) identities. When benchmarked against primary human hepatocytes (PHHs), these HLCs exhibit zone\u2010specific enhanced postnatal metabolic functions. z1\u2010HLCs reveal high albumin and urea production, whereas z3\u2010HLCs show elevated glutamine secretion and cytochrome P450 (CYP) enzyme activity, including CYP3A4, CYP1A2, and CYP2C9. Hallmarks of functional zonation were further confirmed via proteomics, transcriptomics, metabolic assays, and oxygen consumption. z3\u2010HLCs show increased sensitivity to acetaminophen\u2010induced cytotoxicity and distinct immune interactions with primary monocytes. Collectively, the zonated liver organoids provide a promising platform for studying zone\u2010specific liver metabolism, drug metabolism, toxicology, and liver disease, including liver injury.<\/jats:p>","DOI":"10.1002\/adhm.71834","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:45:17Z","timestamp":1791776717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zonation Hallmarks in Human PSC\u2010Derived Hepatic Organoids Integrated into an Immune\u2010Compatible Organ\u2010on\u2010Chip for Liver Injury Modeling"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1642-9250","authenticated-orcid":false,"given":"Aleksandra","family":"Aizenshtadt","sequence":"first","affiliation":[{"name":"Hybrid Technology Hub \u2013 Centre of Excellence Institute of Basic Medical Sciences University of Oslo  Oslo Norway"},{"name":"Department of Immunology and Transfusion Medicine Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4465-9328","authenticated-orcid":false,"given":"Andrea","family":"Dalmao\u2010Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Hybrid Technology Hub \u2013 Centre of Excellence Institute of Basic Medical Sciences University of Oslo  Oslo Norway"},{"name":"Section for Pharmacology and Pharmaceutical Biosciences Department of Pharmacy University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Stokowiec","sequence":"additional","affiliation":[{"name":"Hybrid Technology Hub \u2013 Centre of Excellence Institute of Basic Medical Sciences University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina S\u00e6terdal","family":"K\u00f8murcu","sequence":"additional","affiliation":[{"name":"Hybrid Technology Hub \u2013 Centre of Excellence Institute of Basic Medical Sciences University of Oslo  Oslo Norway"},{"name":"Department of Chemistry University of Oslo  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tharvesh M. 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