{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:58:56Z","timestamp":1790974736536,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2026,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background and Aims<\/jats:title>\n \n Pathogenic variants in\n neuroblastoma amplified sequence<\/jats:italic>\n (\n NBAS<\/jats:italic>\n ) gene causes infantile liver failure type 2 (IFLS2; MIM 616483), characterised by recurrent episodes of liver failure triggered by febrile infections. The underlying pathophysiological mechanisms remain incompletely understood. With this work we try to shed light on the pathomechanism and propose a potential therapeutic option.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n For in\u00a0vitro analyses, human skin fibroblasts were obtained from three individuals with ILFS2 and one healthy control. Cells were cultivated at 37\u00b0C or 40\u00b0C. Western blots were performed to assess NBAS protein and its interaction partners. Furthermore, immunofluorescence and electron microscopy were used to examine morphological changes associated with endoplasmic reticulum (ER) stress. Apoptosis was measured using flow cytometry. The effects of\n N<\/jats:italic>\n \u2010acetylcysteine (NAC) treatment were analysed not only in cultured fibroblasts but also in\u00a0vivo retrospectively in 16 affected individuals.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We demonstrate that elevated temperature induces ER stress in fibroblasts from individuals with\n NBAS<\/jats:italic>\n variants, leading to increased reactive oxygen species (ROS) production and apoptosis. Treatment with the antioxidant NAC, an established therapeutic in acetaminophen\u2010induced liver failure, effectively mitigated oxidative stress and reduced apoptosis in\u00a0vitro. In a retrospective clinical analysis, there was a trend that NAC treatment was associated with reduced severity of hepatic crises, suggesting a potential therapeutic benefit.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our findings link fever\u2010induced ER stress, ROS accumulation, and apoptosis to the pathogenesis of liver failure in NBAS deficiency. NAC attenuates these cellular stress responses and may represent a promising supportive treatment option in NBAS\u2010associated liver failure.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/liv.70762","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T06:37:29Z","timestamp":1782455849000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pathomechanism of Fever\u2010Induced Liver Failure in\n NBAS<\/scp>\n Deficiency and Treatment Effect of\n NAC<\/scp>\n \u2014Observations In\u00a0Vitro and In\u00a0Vivo"],"prefix":"10.1111","volume":"46","author":[{"given":"Tian","family":"Sun","sequence":"first","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-2168","authenticated-orcid":false,"given":"Nicole","family":"Hammann","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Leghlam","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Peters","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cigdem","family":"Arikan","sequence":"additional","affiliation":[{"name":"Department of Paediatric Gastroenterology and Organ Transplant Ko\u00e7 University School of Medicine Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Bedoyan","sequence":"additional","affiliation":[{"name":"Department of Paediatric Gastroenterology and Hepatology UPMC Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tal","family":"Dattner","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-7848","authenticated-orcid":false,"given":"Felix","family":"Distelmaier","sequence":"additional","affiliation":[{"name":"Department of General Paediatrics, Neonatology and Paediatric Cardiology Heinrich\u2010Heine\u2010University, University Children's Hospital D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Fichtner","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7420-4757","authenticated-orcid":false,"given":"Sven F.","family":"Garbade","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5493-3418","authenticated-orcid":false,"given":"Nedim","family":"Had\u017ei\u0107","sequence":"additional","affiliation":[{"name":"King's College Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hegarty","sequence":"additional","affiliation":[{"name":"Paediatric Liver, GI and Nutrition Centre King's College Hospital NHS Foundation Trust London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5971-0862","authenticated-orcid":false,"given":"Andrea","family":"Hellwig","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN) Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne H\u00f8rby","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Rigshospitalet, Paediatrics and Adolescent Medicine Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Jentsch","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8851-672X","authenticated-orcid":false,"given":"Sabine","family":"Jung\u2010Klawitter","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Laass","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Dresden University of Technology Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Lainka","sequence":"additional","affiliation":[{"name":"Department for Paediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Paediatrics II University of Duisburg\u2010Essen, University Hospital Essen Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"M\u00fcnch","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halise Neslihan \u00d6nenli","family":"Mungan","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Division of Paediatric Metabolism Cukurova University Adana Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2873-0032","authenticated-orcid":false,"given":"Moritz","family":"Niesert","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Oehrl","sequence":"additional","affiliation":[{"name":"Department of Dermatology Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Begona","family":"Polo","sequence":"additional","affiliation":[{"name":"Pediatrica Gastrohepathology Unit Hospital Universitario y Polit\u00e9cnico La Fe, University La Fe Hospital Valencia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6344-7799","authenticated-orcid":false,"given":"Knut","family":"Sch\u00e4kel","sequence":"additional","affiliation":[{"name":"Department of Dermatology Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Squires","sequence":"additional","affiliation":[{"name":"Department of Paediatric Gastroenterology and Hepatology UPMC Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00f6lker","sequence":"additional","affiliation":[{"name":"Division of Paediatric Neurology and Metabolic Medicine Heidelberg University Medical Faculty Heidelberg, Centre for Paediatric and Adolescent Medicine Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg 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