Abstract
<title>Abstract</title> <p> <bold>Background/Aims</bold> Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with extremely high short-term mortality. In this study, we aim to assess the methylation level of Takeda G protein-coupled receptor 5 (TGR5) promoter in patients with HBV-ACLF and to explore its prognostic predictive value. <bold>Methods</bold> We enrolled 118 patients with HBV-ACLF, 92 patients with chronic hepatitis B (CHB), and 47 healthy controls (HCs) between September 2024 and November 2025 from three clinical centers in China. TGR5 methylation level in peripheral blood mononuclear cells was quantified using MethyLight. Clinical and laboratory data were also collected for analysis. <bold>Results</bold> TGR5 methylation levels were significantly elevated in patients with HBV-ACLF compared to those with CHB and HCs. Among HBV-ACLF patients, non-survivors exhibited markedly elevated TGR5 methylation levels compared with survivors at both 28 and 90 days. TGR5 methylation level was positively correlated with TBIL, PCT, WBC count and MELD score. Univariate and multivariate logistic regression analyses identified TGR5 methylation level as an independent predictor for both 28-day and 90-day prognosis in HBV-ACLF. Meanwhile, TGR5 methylation level showed superior predictive performance in predicting both 28-day and 90-day mortality compared to the MELD score alone, and their combination further enhanced predictive accuracy. <bold>Conclusions</bold> TGR5 promoter methylation level shows high predictive value for short-term mortality in HBV-ACLF and may serve as a promising biomarker for prognostic assessment. </p>