Single-cell profiling reveals monocyte mitochondrial dysfunction in patients with cirrhosis progressing to acute-on-chronic liver failure

作者：Theresa H. Wirtz, Sara Palomino‐Echeverría, Maike R. Pollmanns, Estefanía Huergo, Felix Schreibing, Johanna Reißing, Cristina Sánchez-Garrido, Cristina López‐Vicario, Ana M. Aransay, Maurizio Baldassare, Giacomo Zaccherini, Enrico Pompili, Martin Schulz, Frank Erhard Uschner, Sabine Klein, Wenyi Gu, Robert Schierwagen, Shantha Valainathan, Annabelle Verbeeck, Daniela Campion, Ilaria Giovo, Kai Markus Schneider, Alexander W. Koch, Rafael Kramann, Tony Bruns, Narsis A. Kiani, Linsey Stiles, Paolo Caraceni, Carlo Alessandria, Richard Moreau, Jonel Trebicka, Joan Clària, Núria Planell, Pierre‐Emmanuel Rautou, Christian Trautwein, David Gómez-Cabrero · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.02.04.25321370 · 被引用次数：1 · 研究领域：Liver Disease and Transplantation、Liver Disease Diagnosis and Treatment、Liver Diseases and Immunity

ABSTRACT Background & Aims Patients with acute decompensation (AD) of cirrhosis are at a high risk of developing acute-on-chronic liver failure (ACLF), a syndrome characterized by multi-organ failure and high short-term mortality. Prospective studies addressing the cellular mechanisms that drive the transition from AD to ACLF are lacking. In this study, we aimed to determine whether peripheral immune cell subsets at hospital admission predict the progression from AD to ACLF and to delineate underlying molecular mechanisms. Approach & Results We prospectively enrolled 63 patients with AD and 15 healthy donors across five European centers, with a 90-day follow-up. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 16 patients with distinct trajectories and 4 controls. Progression to ACLF was associated with expansion of classical monocytes, particularly subcluster “C2”, which specifically displayed impaired energy metabolism with reduced oxidative phosphorylation. Genes encoding respiratory chain Complex IV were markedly downregulated. A C2-derived gene signature was enriched in two large international whole-blood cohorts (PREDICT, n=689; ACLARA, n=521), particularly in patients with bacterial infections, those developing ACLF, and non-survivors. Functional validation by respirometry in an independent AD cohort confirmed declining monocyte Complex IV–dependent oxygen consumption in patients with pre-ACLF. Conclusions We identifie...