Blood multiomics reveal a dysregulated lipid mediator-mitochondrial network associated with the outcome of advanced cirrhosis
The mechanisms driving the progression from acutely decompensated (AD) cirrhosis to acute-on-chronic liver failure (ACLF), a high mortality condition, remain poorly understood. In this study, we integrate multiomics and clinical data from 766 AD patients to construct multiscale, multifactorial response networks associated with two major outcomes: ACLF development and death. Among 291 features, 22 are linked to ACLF development and 16 to mortality. These features constitute a network connecting mitochondrial dysfunction with the accumulation of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE). In vitro validation of this network in human peripheral leukocytes shows that 20-HETE induces mitochondrial oxidative stress and impairs mitochondrial respiration via a GPR75-Akt signaling pathway. Network features also act as early predictors of AD outcomes, a finding validated in an independent cohort of 580 patients. Here, we show a strong link between dysregulated immunomodulatory lipid mediators and mitochondrial dysfunction driving ACLF development and mortality risk in advanced cirrhosis. The mechanisms underlying life-threatening complications in advanced liver disease remain unclear. Here, the authors show that disrupted lipid signals are linked to mitochondrial dysfunction, helping drive these complications and predict patient outcomes.
Authors
- Cristina Sánchez-Garrido
- Esther Titos (ORCID: https://orcid.org/0000-0002-2543-2243)
- Carlos de la Peña-Ramirez
- Cristina López‐Vicario (ORCID: https://orcid.org/0000-0002-6609-8501)
- Bryan J. Contreras
- Ferrán Aguilar (ORCID: https://orcid.org/0000-0002-4367-8095)
- Vicente Arroyo (ORCID: https://orcid.org/0000-0002-2728-1848)
- Fleur Chapus (ORCID: https://orcid.org/0000-0001-6611-9547)
- Sara Palomino‐Echeverría (ORCID: https://orcid.org/0000-0002-0451-3749)
- David Gómez-Cabrero (ORCID: https://orcid.org/0000-0003-4186-3788)
- Marta Duran‐Güell (ORCID: https://orcid.org/0000-0002-3265-395X)
- Estefanía Huergo (ORCID: https://orcid.org/0000-0001-5063-099X)
- Joan Clãria
- María Belén Sánchez-Rodríguez
- Paolo Caraceni
- Wim Laleman
- Glòria Garrabou
- Sebastián Marciano
- Alberto Queiroz Farias
- François Fenaille (ORCID: https://orcid.org/0000-0001-6787-4149)
- Christophe Junot
- Javier Fernández
- Richard Moreau (ORCID: https://orcid.org/0000-0003-0862-403X)
- Pierre-Emmanuel Rautou (ORCID: https://orcid.org/0000-0001-9567-1859)
- Jonel Trebicka (ORCID: https://orcid.org/0000-0002-7028-3881)
- Berta Romero-Grimaldo
- Laura Valls-Roca
- Florence Castelli
Institutions
- Inserm (FR)
- Universidad Pública de Navarra (UPNA) (ES)
- Université Paris Cité (FR)
- University of Münster (DE)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Hôpital Beaujon (FR)
- Hospital Italiano de Buenos Aires (AR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- European Foundation for the Study of Chronic Liver Failure (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Hospital Clínic de Barcelona (ES)
- Centre de Recerca en Economia Internacional (ES)
- Navarrabiomed (ES)
- Grifols (Spain) (ES)
- CEA Paris-Saclay (FR)
- Centre de Recherche sur l'Inflammation (FR)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- King Abdullah University of Science and Technology (SA)
- Universitat de Barcelona (ES)
- University of Bologna (IT)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1038/s41467-026-73386-5
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Institut National de la Santé et de la Recherche Médicale
- Generalitat de Catalunya
- King Abdullah University of Science and Technology
- Westfälische Wilhelms-Universität Münster
- Universitat de Barcelona
- Università di Bologna
- Université Paris-Saclay
- Universidad Pública de Navarra
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
- Grifols
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
- Agencia Estatal de Investigación