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This study elaborates on a multicellular biochip\u2010based liver sinusoid model to mimic MASLD pathomechanisms and investigate the therapeutic effects of drug candidates lanifibranor and resmetirom. Mouse liver primary hepatocytes, hepatic stellate cells, Kupffer cells, and endothelial cells are seeded in a dual\u2010chamber biocompatible liver\u2010on\u2010a\u2010chip (LoC). The LoC is then perfused with circulating immune cells (CICs). Acetaminophen (APAP) and free fatty acids (FFAs) treatment recapitulate acute drug\u2010induced liver injury and MASLD, respectively. As a benchmark for the LoC, multiplex immunofluorescence on livers from APAP\u2010injected and dietary MASLD\u2010induced mice reveals characteristic changes on parenchymal and immune cell populations. APAP exposure induces cell death in the LoC, and increased inflammatory cytokine levels in the circulating perfusate. Under FFA stimulation, lipid accumulation, cellular damage, inflammatory secretome, and fibrogenesis are increased in the LoC, reflecting MASLD. Both injury conditions potentiate CIC migration from the perfusate to the LoC cellular layers. Lanifibranor prevents the onset of inflammation, while resmetirom decreases lipid accumulation in hepatocytes and increases the generation of FFA metabolites in the LoC. This study demonstrates the LoC potential for functional and molecular evaluation of liver disease drug candidates.<\/jats:p>","DOI":"10.1002\/advs.202403516","type":"journal-article","created":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T04:55:26Z","timestamp":1718254526000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Dissecting Acute Drug\u2010Induced Hepatotoxicity and Therapeutic Responses of Steatotic Liver Disease Using Primary Mouse Liver and Blood Cells in a Liver\u2010On\u2010A\u2010Chip Model"],"prefix":"10.1002","volume":"11","author":[{"given":"Hanyang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology Campus Virchow\u2010Klinikum and Campus Charit\u00e9 Mitte Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin  13353 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology Campus Virchow\u2010Klinikum and Campus Charit\u00e9 Mitte Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin  13353 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene Sophia","family":"Kohlhepp","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology Campus Virchow\u2010Klinikum and Campus Charit\u00e9 Mitte Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin  13353 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy Freie Universit\u00e4t Berlin K\u00f6nigin\u2010Luise\u2010Str. 2+4 14195 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Hundertmark","sequence":"additional","affiliation":[{"name":"Department of Hepatology &amp; Gastroenterology Campus Virchow\u2010Klinikum and Campus Charit\u00e9 Mitte Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin  13353 Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed I. 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