A study published in Nature Communications has identified a previously unrecognized molecular network linking dysregulated lipid mediators and mitochondrial dysfunction in patients with acutely decompensated cirrhosis. By integrating lipidomics, metabolomics, cytokine profiling, and clinical data from 766 patients, researchers discovered a network associated with the development of acute-on-chronic liver failure (ACLF) and short-term mortality. The findings provide new insight into the immunometabolic mechanisms driving disease progression and reveal potential biomarkers and therapeutic targets for patients at high risk of poor outcomes.
A systems biology approach to a complex disease
Patients hospitalized with acutely decompensated cirrhosis follow highly variable clinical trajectories. While some stabilize after treatment, others rapidly deteriorate, developing ACLF, a syndrome characterized by multiple organ failures and high short-term mortality.
Despite major advances in understanding the role of systemic inflammation in ACLF, the molecular mechanisms underlying the transition from acute decompensation to organ failure remain incompletely understood. To address this challenge, researchers applied a multi-omics approach integrating targeted lipidomics, untargeted metabolomics, cytokine profiling, and clinical information from 766 patients with decompensated cirrhosis in the framework of the Horizon 2020 DECISION project.
The analysis generated a comprehensive dataset comprising 291 biological and clinical features. From these, researchers shortlisted 22 features associated with ACLF development within 28 days and 16 features associated with 90-day mortality. Network analysis revealed that many of these factors were interconnected within a common biological framework linking altered lipid metabolism and mitochondrial dysfunction.
“ACLF is an extremely complex and multifactorial syndrome, involving systemic inflammation, immune dysfunction, metabolic reprogramming, organ failure, and host–microbiome interactions. Because these processes occur across different biological layers, we felt that focusing on a single omics technology would only provide a partial view of the disease”, said first and corresponding author in the paper Cristina López-Vicario, researcher at Institut d’Investigacions Biomèdiques Pi i Sunyer (IDIBAPS), Spain.
A molecular link between lipid mediators and mitochondrial dysfunction
Researchers identified a molecular network linking elevated levels of 20-hydroxyeicosatetraenoic acid (20-HETE), a bioactive lipid mediator derived from arachidonic acid metabolism, with the accumulation of acylcarnitines, established markers of mitochondrial dysfunction.
Patients who later developed ACLF showed evidence of both increased 20-HETE concentrations and metabolic signatures consistent with mitochondrial dysfunction. These findings suggest that alterations in lipid signaling and cellular energy metabolism are closely intertwined during disease progression.
To validate these observations, researchers performed mechanistic studies in human peripheral leukocytes, a specialized type of immune cells. They demonstrated that exposure to 20-HETE induced mitochondrial oxidative stress and impaired mitochondrial respiration through activation of the GPR75–Akt signaling pathway.
“These findings move beyond association and provide mechanistic evidence that dysregulated lipid mediators are linked to impaired mitochondrial function in immune cells”, added López-Vicario.
The results support the concept that immunometabolic dysfunction—a combination of immune dysregulation and metabolic impairment—plays a central role in the progression from acute decompensation to ACLF.
Beyond inflammation: A new perspective on disease progression
While systemic inflammation has long been considered a hallmark of advanced cirrhosis, the study suggests that metabolic alterations may play a more prominent role than previously appreciated.
Interestingly, the network associated with ACLF development did not reveal strong direct links between mitochondrial dysfunction and classical inflammatory cytokines. Instead, the strongest associations involved lipid mediators and metabolites involved in energy metabolism.
The researchers also identified a second pathway associated with poor outcomes involving sphingosine-1-phosphate (S1P), a signaling lipid that regulates lymphocyte trafficking. Reduced circulating S1P levels were strongly associated with ACLF development and accompanied by alterations in genes involved in its synthesis, degradation, and signaling.
These findings may help explain the severe lymphopenia (a marked reduction in circulating lymphocytes) frequently observed in patients with advanced cirrhosis and provide additional evidence that immune dysfunction in these patients extends beyond inflammatory signaling alone.
Predicting outcomes before clinical deterioration
The study also identified several molecular features capable of predicting ACLF development and short-term mortality before overt clinical deterioration occurred.
Importantly, these predictive markers were validated in an independent cohort of 580 patients, demonstrating their robustness across different patient populations.
Several of the identified features performed as well as, or better than, established prognostic scores currently used in clinical practice. The findings raise the possibility that future biomarker panels integrating metabolic and lipidomic information could improve risk stratification at hospital admission and allow earlier intervention in high-risk patients.
“Early identification of patients at risk remains one of the greatest challenges in managing advanced cirrhosis,” said senior author Joan Clària, Group Leader of the Inflammation and Liver Disease group at IDIBAPS, Spain., senior consultant of Biochemical and Molecular Genetics Service and CIBERehd member. “Our findings suggest that molecular signatures reflecting underlying disease mechanisms may help identify vulnerable patients before organ failure develops”, he added.
Implications for future research and treatment
This study represents one of the largest and most comprehensive multi-omics investigations conducted in advanced cirrhosis to date. The integration of large-scale molecular datasets with clinical outcomes and mechanistic validation experiments provides a framework for understanding the biological pathways that drive progression toward ACLF and death.
Beyond their prognostic value, the identified networks also point toward potential therapeutic targets. In particular, the link between 20-HETE and mitochondrial dysfunction raises the possibility that interventions targeting lipid mediator pathways could help preserve cellular metabolism and prevent organ failure.
“Looking further ahead, these results highlight the potential of network medicine in hepatology. Rather than targeting single molecules in isolation, future therapies may aim to correct interconnected metabolic and inflammatory pathways that drive ACLF. Such strategies could transform ACLF management from largely supportive care toward mechanism-based prevention and treatment”, concluded Clària.
As the field increasingly embraces systems biology approaches, studies such as this demonstrate how integrating multiple layers of biological information can reveal disease mechanisms that remain invisible when examined in isolation. Together, these findings reinforce the emerging concept that immunometabolic dysfunction is a central driver of poor outcomes in advanced cirrhosis and may ultimately provide new opportunities to improve patient survival and quality of life.
Study of reference
C López-Vicario, F Aguilar, F Chapus, C de la Peña-Ramirez, F Fenaille, F Castelli, M Duran-Güell, B J. Contreras, B Romero-Grimaldo, MB Sánchez-Rodríguez, L Valls-Roca, G Garrabou, S Palomino-Echeverria, E Huergo, C Sanchez-Garrido, W Laleman, D Gómez-Cabrero, A Queiroz Farias, S Marciano, P Caraceni, J Trebicka, J Fernández, C Junot, E Titos, R Moreau, V Arroyo, P-E Rautou, J Clària; On behalf of the DECISION Consortium. Blood multiomics reveal a dysregulated lipid mediator-mitochondrial network associated with the outcome of advanced cirrhosis. Nat Commun 2026. E pub ahead of print. DOI: 10.1038/s41467-026-73386-5
