Xue-Fei Wei,1 Jing Wang,1 Ji-Hui Li,1 Ying Zhang,1 Hui-Hui Liu,1 Na Wang,2 Xue-Mei Jiang,3 Hui Lyu,4 Yu-Chen Fan,1 Kai Wang1,2 

1Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Hepatology, Qilu Hospital of Shandong University (Qingdao), Qingdao, Shandong, People’s Republic of China; 3Department of Hepatology, Shandong Public Health Clinical Center, Jinan, Shandong, People’s Republic of China; 4Department of Severe Liver Disease, Shandong Public Health Clinical Center of Shandong University, Jinan, Shandong, People’s Republic of China

Correspondence: Kai Wang, Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Jinan, Shandong, People’s Republic of China, Email wangdoc2010@163.com

Purpose: Death receptor 3(DR3) is a key factor in the regulation of immune response and inflammatory diseases. The study aimed to quantitatively assess the levels of DR3 promoter methylation, investigate the correlation between DR3 promoter methylation and its expression, and develop a prognosis prediction model incorporating clinical indicators for acute-on-chronic hepatitis B liver failure (ACHBLF).
Methods: DR3 expression in peripheral blood mononuclear cells (PBMCs), as well as methylation levels, were detected using Methylight and quantitative polymerase chain reaction(qPCR) in a total of 362 patients and volunteers. Univariate, LASSO regression, and multifactorial analyses were performed to identify factors associated with 90-day outcomes in patients with ACHBLF. A clinical prediction model was constructed using DR3 promoter methylation levels and clinical parameters. Receiver Operating Characteristic Curve (ROC) was used to evaluate the model’s discriminative ability. The Hosmer-Lemeshow (H-L) goodness-of-fit test and Decision Curve Analysis (DCA) were employed to assess the model’s calibration and clinical practicability. The SHapley Additive explanations (SHAP) method was employed to interpret the top-performing model.
Results: The results showed that DR3 methylation levels were significantly lower in ACHBLF patients. Furthermore, non-survivors exhibited lower DR3 methylation levels than survivors and higher mRNA levels than survivors. A clinical model incorporating prothrombin activity (PTA), procalcitonin (PCT), and the percentage of methylation reference (PMR) value of DR3 was developed to predict ACHBLF prognosis. The model demonstrated good performance in predicting 3-month mortality. The goodness-of-fit test and DCA confirmed the model’s robust calibration and clinical applicability.
Conclusion: Abnormal DR3 promoter methylation exists in patients with ACHBLF. The integration of PMR DR3, PTA, and PCT into a short-term prognostic model holds significant promise for clinical application in predicting ACHBLF outcomes.

Keywords: DR3, ACHBLF, methylation, prognosis, noninvasive model