Rearrangement of the liver ubiquitome and NEDDylome in metabolic dysfunction-associated steatotic liver disease
The remodeling of the liver proteome, driven by dynamic ubiquitin-like post-translational modifications (PTMs) such as ubiquitination and NEDDylation, is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD). These PTMs enable rapid adaptation to environmental challenges by modulating protein stability and function. Using transgenic biotinylated ubiquitin and biotinylated NEDD8 mice, we profiled the hepatic ubiquitome and NEDDylome in a diet-induced MASLD model. Quantitative mass spectrometry identified over 1400 ubiquitinated proteins, with more than 600 proteins significantly altered in MASLD. Ubiquitinated proteins were enriched in processes related to endoplasmic reticulum and peroxisomal lipid metabolism, while NEDDylated targets primarily localized to mitochondrial pathways. Proteomic analysis revealed impaired proteasome function, endoplasmic reticulum stress, and mitochondrial dysfunction, suggesting that dysregulation of ubiquitin-like PTMs plays a critical role in MASLD. Our findings provide new insights into the distinct roles of ubiquitin and NEDD8 in MASLD. Further exploration of PTM crosstalk will enhance our understanding of MASLD pathophysiology.
Authors
- Leire Uraga-Gracianteparaluceta
- Rosa Barrio (ORCID: https://orcid.org/0000-0002-9663-0669)
- Jesús M. Arizmendi (ORCID: https://orcid.org/0000-0002-1412-4042)
- Fernando Lopitz‐Otsoa (ORCID: https://orcid.org/0000-0001-8452-6939)
- Marina Serrano‐Maciá (ORCID: https://orcid.org/0000-0003-4183-6384)
- Mikel Azkargorta (ORCID: https://orcid.org/0000-0001-9115-3202)
- Ibon Martínez‐Arranz (ORCID: https://orcid.org/0000-0001-9483-8426)
- Kerman Aloria (ORCID: https://orcid.org/0000-0001-7268-7700)
- Benoît Lectez (ORCID: https://orcid.org/0000-0001-9796-1606)
- Ugo Mayor (ORCID: https://orcid.org/0000-0003-2812-8287)
- Maria Luz Martínez‐Chantar (ORCID: https://orcid.org/0000-0002-6446-9911)
- James D. Sutherland (ORCID: https://orcid.org/0000-0003-3229-793X)
- Teresa C. Delgado
Institutions
- Ikerbasque (ES)
- University of the Basque Country (ES)
- BioCruces Health research Institute (ES)
- CIC bioGUNE (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Zubiola (Spain) (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
Publication Details
- Journal
- npj gut and liver.
- Published
- 2025-08-05
- DOI
- https://doi.org/10.1038/s44355-025-00032-0
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Gilead Sciences
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Eusko Jaurlaritza
- Ministerio de Ciencia e Innovación
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
- Fundação para a Ciência e a Tecnologia
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación