Single-Cell Multimodal Analysis Reveals the Dynamic Immunopathogenesis of HBV-ACLF: Gut | 2026 | DOI: 10.1136/gutjnl-2024-333308

Introduction

Acute-on-chronic liver failure (ACLF) is a highly dynamic and life-threatening syndrome marked by intense systemic inflammation and immune dysregulation. In Asia, hepatitis B virus (HBV) reactivation is a leading trigger of ACLF. However, the longitudinal immune trajectories that drive progression, recovery, or deterioration in HBV-related ACLF (HBV-ACLF) remain poorly defined. This study used single-cell multiomics to map immune evolution during the disease course.

Summary

In this longitudinal analysis of 17 hospitalised patients with HBV-ACLF and 15 controls, single-cell RNA sequencing and proteomics of peripheral blood mononuclear cells revealed stage-specific immune reprogramming. Early ACLF was characterised by expansion of VCAN⁺CD14⁺ monocytes with activated interferon-stimulated genes, fuelling an inflammatory surge following HBV relapse. As the disease progressed, hyperinflammatory CXCR2⁺ neutrophils and CD163⁺ monocytes became enriched and were strongly associated with deterioration. Cytotoxic T cells were reduced and functionally exhausted in progressive disease, partly driven by immunosuppressive CXCR2⁺ neutrophils. Pharmacologic CXCR2 inhibition reduced neutrophil infiltration and restored cytotoxic T-cell function in experimental models, suggesting therapeutic potential.

Six immune cellular modules were identified for patient stratification. CM2 and CM6 predicted adverse outcomes, while CM3 marked a potential early therapeutic window. This study provides a dynamic immune atlas of HBV-ACLF and supports immune-targeted precision strategies for risk stratification and intervention.