This longitudinal single-cell multiomics study provides a detailed immune roadmap of HBV-related acute-on-chronic liver failure (HBV-ACLF), a syndrome marked by profound immune dysregulation and high short-term mortality. Using single-cell RNA sequencing and proteomics from 45 peripheral blood samples (across progressive, stable, and recovering ACLF courses) and appropriate controls, investigators identified a dynamic immune trajectory.
This longitudinal single-cell multiomics study provides a detailed immune roadmap of HBV-related acute-on-chronic liver failure (HBV-ACLF), a syndrome marked by profound immune dysregulation and high short-term mortality.
Using single-cell RNA sequencing and proteomics from 45 peripheral blood samples (across progressive, stable, and recovering ACLF courses) and appropriate controls, investigators identified a dynamic immune trajectory.
Key findings:
Early phase (ACLF-1): Expansion of VCAN⁺CD14⁺ inflammatory monocytes driven by HBV relapse. These cells exhibited strong interferon-stimulated gene activation, fueling the early inflammatory storm.
Progressive phase: Apoptotic hepatocytes triggered expansion of CXCR2⁺ neutrophils and CD163⁺ monocytes, strongly associated with disease deterioration.
Immune exhaustion: Cytotoxic T cells were markedly reduced and functionally impaired in progressive patients.
CXCR2⁺ neutrophils demonstrated immunosuppressive activity, directly inducing T-cell exhaustion.
Importantly, pharmacologic CXCR2 inhibition in ACLF mouse models reduced neutrophil infiltration, restored cytotoxic T-cell function, and improved outcomes—highlighting a promising therapeutic target.
Six immune cellular modules (CMs) were identified for risk stratification, with CM2 and CM6 predicting outcomes, and CM3 suggesting a potential early intervention window.
Clinical implication: HBV-ACLF progression is driven by a shift from hyperinflammation to neutrophil-mediated immune paralysis. Targeting the CXCR2 axis may represent a rational strategy for precision immunomodulation in ACLF.
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