Cristina López-Vicario

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.

Background & Aims: Patients with acutely decompensated cirrhosis (ADC) present severe immune dysfunction characterized by smoldering systemic inflammation and persistent immunosuppression rendering them at increased risk of bacterial infections and acute-on-chronic liver failure (ACLF). Approach & Results: We explored the profile of 98 immunomodulatory lipid mediators in ADC patients with and without ACLF and their effects on leukocyte function. We performed LC-MS/MS-based lipidomics of 308 plasma samples longitudinally collected from 93 ADC patients with and without ACLF and integrated expression and flow cytometry data with functional assays in leukocytes. Lipidomics identified the linoleic acid-derived leukotoxin 9,10-dihydroxy-12-octadecenoic acid (9,10-DiHOME) as the only lipid mediator elevated in ACLF. 9,10-DiHOME levels followed the disease severity course and peaked when patients acquired infections and developed ACLF. Leukocytes from ADC patients showed increased expression of soluble epoxide hydrolase (sEH), the enzyme responsible for 9,10-DiHOME biosynthesis. In polymorphonuclear leukocytes, 9,10-DiHOME impaired degranulation, phagocytosis, and respiratory burst capacities. In mononuclear leukocytes, this lipid mediator induced the expression of the immunosuppressive marker MerTK, impaired their ability to produce cytokines in response to LPS and disrupted mitochondrial dynamics and autophagic responses. Inhibition of sEH in vivo reduced immunosuppressive responses in peritoneal macrophages and significantly attenuated MerTK expression in liver macrophages. Conclusions: These findings indicate that increased levels of the leukotoxin 9,10-DiHOME weakens immune-cell defensive responses and position sEH as a potential drug target in ADC.

Hyaluronic acid (HA) is a major glycosaminoglycan in the hepatic extracellular matrix and pericellular space, playing a critical role in maintaining liver architecture and regulating cell–matrix interactions. In chronic liver disease, regardless of etiology, dysregulated HA metabolism, particularly the generation and accumulation of low-molecular-weight HA (LMW-HA), has been implicated in fibrogenesis, immune dysregulation, and hepatocellular carcinogenesis via receptor-mediated pathways involving lymphocyte homing receptor (CD44), receptor for hyaluronan-mediated motility (RHAMM), and Toll-like receptors (TLRs). This review synthesizes current evidence on HA biosynthesis, turnover, and signaling, emphasizing its dual role as a structural scaffold and as an active modulator of immune responses and tumor progression in chronic liver disease. Given the rising global burden of metabolic liver disease, and in line with our recent findings that small HA fragments are elevated in obesity and promote low-grade, TLR-dependent activation of innate immune cells, we emphasize metabolic dysfunction-associated steatotic liver disease (MASLD) as a highly prevalent and clinically relevant setting to examine HA-driven immunomodulation during progression to advanced fibrosis and hepatocellular carcinoma (HCC) and to consider therapeutic strategies targeting HA synthesis, turnover, or receptor signaling.

Hyaluronic acid (HA) is a major glycosaminoglycan in the hepatic extracellular matrix and pericellular space, playing a critical role in maintaining liver architecture and regulating cell-matrix interactions. In chronic liver disease, particularly in metabolic dysfunction-associated steatotic liver disease (MASLD), aberrant HA metabolism, especially the accumulation of low-molecular-weight HA, contributes to fibrogenesis, immune dysregulation, and hepatocellular carcinoma development through receptor-mediated pathways involving CD44, RHAMM, and Toll-like receptors. This review synthesizes current evidence on HA biosynthesis, turnover, and signaling, emphasizing its dual role as a structural scaffold and as an active modulator of immune responses and tumor progression in chronic liver disease. We place special emphasis on its immunomodulatory function during the progression from MASLD to HCC and discuss its emerging relevance as therapeutic target. Potential strategies to counteract HA-mediated pathology, including inhibition of HA synthesis, enzymatic degradation, and receptor blockade, are also critically examined.

Background: Acute-on-chronic liver failure (ACLF), which develops in patients with acutely decompensated cirrhosis, is characterized by multiple extrahepatic organ failures leading to high short-term mortality. Although major advances in the understanding of ACLF have been accomplished in the last years, the understanding of driving mechanisms underlying ACLF is hindered by the lack of proper animal models that faithfully reproduce both the systemic hyperinflammatory response and the full spectra of extrahepatic organ failures present in this condition. Methods: ACLF was induced by acute induction of polymicrobial peritonitis secondary to the ligation and puncture of the cecum (CLP) in mice with chronic carbon tetrachloride (CCl₄)-induced cirrhosis. The study included three groups: CCl₄+CLP (n=10) mice with cirrhosis which underwent CLP surgery; CCl₄+sham mice (n=10) and control mice (n=10). Results: As compared to CCl₄+sham, CCl₄+CLP mice had higher short-term mortality and exhibited more severe hypoalbuminemia and hyperbilirubinemia, significantly higher AST and GGT levels and higher liver inflammatory burden. CCl₄+CLP mice also showed increased serum creatinine and BUN levels and up-regulated expression of Kim-1, Il-6 and Tnf in the kidney, lower oxygen saturation (SpO₂), higher serum renin concentration, higher international normalized ratio (INR) and worse neurological behavior test scores than CCl₄+sham and control mice. In addition, CCl₄+CLP mice showed widespread bacterial tissue colonization and exhibited increased serum cytokine levels, which correlated with the intensity of organ impairments. Conclusion: The CCl₄+CLP model reproduces the full spectra of extrahepatic organ impairments present in patients with ACLF and represents an optimized murine model to experimentally explore the pathophysiology of this disease as well as new therapeutic approaches.

Patient heterogeneity represents a significant challenge for both individual patient management and clinical trial design, especially in the context of complex diseases. Most existing clinical classifications are based on scores built to predict patients’ outcomes. These classical methods may thus miss features that contribute to heterogeneity without necessarily translating into prognostic implications. To address patient heterogeneity at hospital admission, we developed ClustALL, a computational pipeline designed to handle common clinical data challenges such as mixed data types, missing values, and collinearity. ClustALL also facilitates the unsupervised identification of multiple and robust stratifications. We applied ClustALL to a prospective European multicentre cohort of patients with acutely decompensated cirrhosis (AD) (n=766), a highly heterogeneous disease. ClustALL identified five robust stratifications for patients with AD, using only data at hospital admission. All stratifications included markers of impaired liver function and number of organ dysfunction or failure, and most included precipitating events. When focusing on one of these stratifications, patients were categorized into three clusters characterized by typical clinical features but also having a prognostic value. Re-assessment of patient stratification during follow-up delineated patients’ outcomes, with further improvement of the prognostic value of the stratification. We validated these findings in an independent prospective multicentre cohort of patients from Latin America (n=580). In conclusion, this study developed ClustALL, a novel and robust stratification method capable of addressing challenges tied to intricate clinical data and applicable to complex diseases. By applying ClustALL to patients with AD, we identified three patient clusters, offering insights that could guide future clinical trial design.

Background and Aim: Injury to hepatocyte mitochondria is common in metabolic dysfunction‐associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid–derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency. Approach and Results: The study was performed in transgenic mice for the fat‐1 gene, which allows the endogenous replacement of the membrane omega‐6–polyunsaturated fatty acid (PUFA) composition by omega‐3–PUFA. Transmission electron microscopy revealed that hepatocyte mitochondria of fat‐1 mice had more abundant intact cristae and higher mitochondrial aspect ratio. Fat‐1 mice had increased expression of oxidative phosphorylation complexes I and II and translocases of both inner (translocase of inner mitochondrial membrane 44) and outer (translocase of the outer membrane 20) mitochondrial membranes. Fat‐1 mice also showed increased mitofusin‐2 and reduced dynamin‐like protein 1 phosphorylation, which mediate mitochondrial fusion and fission, respectively. Mitochondria of fat‐1 mice exhibited enhanced oxygen consumption rate, fatty acid β‐oxidation, and energy substrate utilization as determined by high‐resolution respirometry, [1‐¹⁴C]‐oleate oxidation and nicotinamide adenine dinucleotide hydride/dihydroflavine‐adenine dinucleotide production, respectively. Untargeted lipidomics identified a rich hepatic omega‐3–PUFA composition and a specific docosahexaenoic acid (DHA)–enriched lipid fingerprint in fat‐1 mice. Targeted lipidomics uncovered a higher content of DHA‐derived lipid autacoids, namely resolvin D1 and maresin 1, which rescued hepatocytes from TNFα‐induced mitochondrial dysfunction, and unblocked the tricarboxylic acid cycle flux and metabolic utilization of long‐chain acyl‐carnitines, amino acids, and carbohydrates. Importantly, fat‐1 mice were protected against mitochondrial injury induced by obesogenic and fibrogenic insults. Conclusion: Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.