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  3. Pathomechanism of Fever-Induced Liver Failure in NBAS Deficiency and Treatment Effect of NAC—Observations In Vitro and In Vivo

Pathomechanism of Fever-Induced Liver Failure in NBAS Deficiency and Treatment Effect of NAC—Observations In Vitro and In Vivo

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Sun T.
  • Hammann N.
  • Leghlam L.
  • Peters B.
  • Arikan C.
  • Bedoyan S.M.
  • Chen Q.
  • Dattner T.
  • Distelmaier F.
  • Fichtner A.
  • Garbade S.F.
  • Hadžic N.
  • Hegarty R.
  • Hellwig A.
  • Jørgensen M.H.
  • Jentsch C.
  • Jung-Klawitter S.
  • Laass M.
  • Lainka E.
  • Münch H.
  • Mungan H.N.Ö.
  • Niesert M.
  • Oehrl S.
  • Schäkel K.
  • Squires J.E.
  • Kölker S.
  • Hoffmann G.F.
  • Staufner C.
  • Lenz D.

Grupos

Abstract

Background and Aims: Pathogenic variants in neuroblastoma amplified sequence (NBAS) 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. Methods: For in vitro analyses, human skin fibroblasts were obtained from three individuals with ILFS2 and one healthy control. Cells were cultivated at 37°C or 40°C. 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-acetylcysteine (NAC) treatment were analysed not only in cultured fibroblasts but also in vivo retrospectively in 16 affected individuals. Results: We demonstrate that elevated temperature induces ER stress in fibroblasts from individuals with NBAS variants, leading to increased reactive oxygen species (ROS) production and apoptosis. Treatment with the antioxidant NAC, an established therapeutic in acetaminophen-induced liver failure, effectively mitigated oxidative stress and reduced apoptosis in vitro. 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. Conclusions: Our findings link fever-induced 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-associated liver failure. © 2026 The Author(s). Liver International published by John Wiley & Sons Ltd.

Datos de la publicación

ISSN/ISSNe:
1478-3223, 1478-3231

LIVER INTERNATIONAL  WILEY

Tipo:
Article
Páginas:
-
PubMed:
42358045
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
2,064 SCImago ℠
Cuartil:
Q1 SCImago ℠

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Keywords

  • Acetylcysteine; Antioxidants; Apoptosis; Cells, Cultured; Child, Preschool; Endoplasmic Reticulum Stress; Female; Fever; Fibroblasts; Humans; Infant; Liver Failure; Male; Neoplasm Proteins; Oxidative Stress; Reactive Oxygen Species; Retrospective Studies; acetylcysteine; antioxidant; NBAS protein, human; reactive oxygen metabolite; tumor protein; apoptosis; cell culture; complication; drug effect; drug therapy; endoplasmic reticulum stress; etiology; female; fever; fibroblast; human; infant; liver failure; male; metabolism; oxidative stress; preschool child; retrospective study

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