{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:16:34Z","timestamp":1760231794429,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T00:00:00Z","timestamp":1652140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"ERC Advanced Grant (AdG)","doi-asserted-by":"publisher","award":["742020","2018-05766"],"award-info":[{"award-number":["742020","2018-05766"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Swedish Research Council","award":["742020","2018-05766"],"award-info":[{"award-number":["742020","2018-05766"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of, e.g., novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids, wherein long slender filaments form after chronic treatment with four different drugs, of which three are PPAR\u03b1 antagonists. The morphology of the thorns varies between donors and the compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471 revealed changes in gene and protein expression, such as those in the spheroids. In addition, similar changes in keratin expression were seen following the treatment of hepatotoxic drugs, including aflatoxin B1, paracetamol, chlorpromazine, cyclosporine, and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM-derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems, such as the spheroids.<\/jats:p>","DOI":"10.3390\/cells11101597","type":"journal-article","created":{"date-parts":[[2022,5,10]],"date-time":"2022-05-10T08:31:55Z","timestamp":1652171515000},"page":"1597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte Thorns, A Novel Drug-Induced Stress Response in Human and Mouse Liver Spheroids"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4414-8544","authenticated-orcid":false,"given":"Chris S.","family":"Pridgeon","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3862-8621","authenticated-orcid":false,"given":"Dian P.","family":"Bolhuis","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filip","family":"Milosavljevi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Manojlovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1287-0906","authenticated-orcid":false,"given":"\u00c1kos","family":"V\u00e9gv\u00e1ri","sequence":"additional","affiliation":[{"name":"Proteomics Biomedicum, Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimiliano","family":"Gaetani","sequence":"additional","affiliation":[{"name":"Chemical Proteomics, Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden"},{"name":"Unit of Chemical Proteomics, Science for Life Laboratory (SciLifeLab), 171 65 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marin M.","family":"Juki\u0107","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"},{"name":"Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-9079","authenticated-orcid":false,"given":"Magnus","family":"Ingelman-Sundberg","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, 171 65 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bell, C.C., Hendriks, D.F.G., Moro, S.M.L., Ellis, E., Walsh, J., Renblom, A., Fredriksson Puigvert, L., Dankers, A.C.A., Jacobs, F., and Snoeys, J. 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