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

Abstract

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.