Abstract
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.
Acknowledgements
We thank Drs. Anna Bosch and Lidia García-Campmany for their support and Mr Albert Salvatella, Ms Inés Vanhille and the Animal Experimentation Unit of the University of Barcelona (CCiTUB) for their technical assistance.
Funding
This work received funding from the European Union’s Horizon 2020 research and innovationprogramme under grant agreement No 847949 and was made possible through access to data andsamples generated by the PREDICT and the ACLARA studies funded by the EF CLIF. JC laboratoryis a Consolidated Research Group recognized by the Generalitat de Catalunya (2021 SGR 01323) andis supported by Ministerio de Ciencia, Innovación y Universidades/Agencia Estatal InvestigaciónMCIU/AEI (PID2022-138970OB-I00 10.13039/501100011033/FEDER, UE) and the Centro deInvestigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). GGlaboratory is supported by the Catalan Government (2021-SGR-01423), the Fondo de InvestigacionesSanitarias del Instituto de Salud Carlos III (ISCIII) (Grant codes PI21/00935 and PI24/00428) and theCentro de Investigación Biomédica en 988 Red de Enfermedades Raras (CIBERER), initiatives of ISCIIIand FEDER. LV-R is supported by FI22/00142 (ISCIII-NextGenerationEU). The funders had noinfluence on study design, data collection and analysis, decision to publish or preparation of themanuscript.
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López-Vicario, C., Aguilar, F., Chapus, F. et al. Blood multiomics reveal a dysregulated lipid mediator-mitochondrial network associated with the outcome of advanced cirrhosis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73386-5
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DOI: https://doi.org/10.1038/s41467-026-73386-5
