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

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. METHODS: We prospectively enrolled 63 patients with AD and 15 healthy donors across five European centres, 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. RESULTS: Progression to ACLF was associated with expansion of classical monocytes, particularly subcluster "C2", which specifically displayed impaired energy metabolism with reduced oxidative phosphorylation (p<0.001). A C2-derived gene signature (18 genes) 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 (p<0.001). Functional validation by respirometry in an independent AD cohort confirmed declining monocyte Complex IV-dependent oxygen consumption in patients with pre-ACLF (p<0.05). CONCLUSIONS: We identified and validated a distinct monocyte subpopulation with defective energy metabolism in patients with AD with poor outcomes, supporting a link between monocyte bioenergetic dysfunction and ACLF development. Impact and Implications:The cellular mechanisms that drive progression from acute decompensation (AD) to acute-on-chronic liver failure (ACLF) remain poorly understood, limiting the development of effective strategies for therapeutic intervention. By integrating prospective single-cell transcriptomics, functional bioenergetic analyses, and validation in independent multicentre cohorts, we identified a distinct monocyte subset characterized by impaired oxidative phosphorylation that is associated with subsequent ACLF development. These findings are relevant to clinicians and researchers because they suggest that immune-metabolic dysfunction emerges before overt ACLF and may contribute to disease progression. While further mechanistic and prospective validation studies are required, our results provide a framework for the investigation of monocyte bioenergetics as a potential therapeutic target in patients with decompensated cirrhosis.