ETS2 alleviates acute-on-chronic liver failure by suppressing excessive inflammation

Area of Science:

• Hepatology and Immunology
• Molecular Biology

Background:

• Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe condition with high mortality.
• The role of the transcription factor ETS2 in HBV-ACLF pathogenesis is not well understood.

Purpose of the Study:

• To investigate the molecular mechanism of ETS2 in HBV-ACLF.
• To evaluate ETS2 as a potential prognostic biomarker and therapeutic target for HBV-ACLF.

Main Methods:

• RNA sequencing of peripheral blood mononuclear cells from HBV-ACLF patients (n=50).
• Area-under-ROC analysis for mortality prediction.
• Myeloid-specific ETS2 deficiency in mouse models of liver failure.
• ETS2 knockout in macrophages treated with HMGB1 and lipopolysaccharide (LPS).

Main Results:

• ETS2 expression was significantly elevated in HBV-ACLF patients compared to controls (p < 0.001).
• ETS2 showed high predictive value for 28-day (0.908) and 90-day (0.773) mortality.
• High ETS2 expression correlated with upregulated innate immune responses (monocytes, neutrophils, inflammation pathways).
• ETS2 deficiency in mice worsened liver failure and increased pro-inflammatory cytokines (IL-6, IL-1β, TNF-α).
• ETS2 knockout in macrophages reduced IL-6 and IL-1β levels induced by HMGB1/LPS, an effect reversed by an NF-κB inhibitor.

Conclusions:

• ETS2 is a potential prognostic biomarker for HBV-ACLF patients.
• ETS2 alleviates liver failure by suppressing the HMGB1/LPS-triggered inflammatory response.
• ETS2 represents a potential therapeutic target for HBV-ACLF.