Multi-Omics Gene Signatures Predict Disease Trajectory in a Cholestasis-Based ACLF Mouse Model

Acute-on-chronic liver failure (ACLF) is a severe complication of chronic liver diseases, often fatal, with poorly understood pathomechanism and prognosis. We aiming to develop a novel in vivo model using aged Abcb4 knockout (KO) mice (cholestasis-based) treated with a sublethal dose of CCl₄, featuring the ACLF. Two distinct outcomes – good and poor prognosis – based on survivability and necrosis patterns were reported. Mice with good prognosis exhibited massive hepatic necrosis initially, followed by recovery, whereas poor prognosis mice showed minimal necrosis and die within 24h. To investigate the ACLF pathomechanism, we conducted a longitudinal multiomic analysis integrating transcriptomic and proteomic data. Using Multi-Omics Factor Analysis (MOFA), we identified two conserved dynamic trajectories. The "recovery trajectory" showed upregulation of candidates involved in metabolism, including Acot1, Hmgcs1, and G6pc, suggesting an adaptive metabolic response promoting recovery. The "injury trajectory" involved regulators of inflammation and injury pathways, i.e. Fgg, Itgam, and Cd63, indicating an immune response linked to poor outcome. Validation using public datasets demonstrated that the injury trajectory correlated with increasing chronic liver disease severity in ACLF patients. Then, we performed ROC analysis of transcriptomic and proteomic changes at 24h post-CCl₄, identifying nine prognostic biomarkers, including Abhd4, Cd14, and Slc38a2. Using Single-nuclei RNA-sequencing we identified clusters of hepatocytes, cholangiocytes, Kupffer cells, endothelial cells, and stellate cells, with genes involved in cell death, acute phase response, and ROS function enriched in the poor prognosis. Our multiomics approach identified novel ACLF-related biomarkers and underscore further exploration of secreted proteins, paving the way for prognosis, and personalized interventions.

Publication History

Article published online:
20 January 2025