Single‐Cell Analysis of Hepatic Non‐Parenchymal Cells Reveals Endothelial Dysfunction and Altered Endothelial and B Cell Communication in Acute‐on‐Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) is a fatal syndrome defined by hepatic decompensation and systemic inflammation, yet the underlying cellular networks remain elusive. Here, we established an ACLF mouse model recapitulating clinical hallmarks and performed single-cell RNA sequencing (scRNA-seq) on hepatic non-parenchymal cells (NPCs). We identified 30 cell clusters and observed profound spatial remodeling of NPCs driven by pro-inflammatory mediators. Endothelial cells (ECs) underwent a critical transition from homeostasis to dysfunction, marked by mitochondrial damage and activation of NF-κB and MAPK pathways. Ligand-receptor interactome analysis identified dysfunctional ECs as central hubs driving global network reconfiguration, primarily via the Lgals9-Ighm/Cd45/Cd44 axes, alongside the suppression of homeostatic signals (Cd55 and APP). Furthermore, we mapped B cell lineage trajectories and validated the spatial co-localization of EC and B-cell interactions through Lgals9-Ighm. This study defines the EC and B-cell communication landscape and suggests that the Lgals9-Ighm axis may play a critical role in ACLF progression, representing a potential candidate for therapeutic intervention.