Research Progress on the Mechanism and Targeted Intervention of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1)-Mediated “Inflammation-Apoptosis-Metabolism-Microcirculation” Regulatory Network in Hepatitis B-Associated Liver Failu

Chao Cui,1 Yu Sun,2 Kaiyue Zhang,2 Jingfei Shi,3 Kai Wang,2,4 Shuai Gao4 1Scientific Research Department, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, People’s Republic of China; 2Department of Infectious Disease, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, People’s Republic of China; 3Department of Clinical and Basic Medicine, Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Hepatology, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Kai Wang, Email [email protected]; Shuai Gao, Email [email protected]: Hepatitis B-associated liver failure (HBV-LF) is a severe hepatic disease induced by hepatitis B virus infection, characterized by massive hepatocyte necrosis, rapid liver dysfunction, uncontrolled inflammation, bile acid metabolism disorders and immune microenvironment imbalance. It has a high short-term mortality of 40%– 70% worldwide. Current mainstream treatments, including antiviral and organ support therapies, only control viral replication and maintain organ function, but cannot effectively reverse the excessive inflammatory cascade and metabolic disorders that drive HBV-LF progression. This review systematically summarizes the molecular mechanisms by which GPBAR1 regulates the four core pathological processes of HBV-LF: uncontrolled inflammation, massive hepatocyte apoptosis, bile acid metabolism disorders and hepatic microcirculation disturbance, and clarifies its value as a potential therapeutic target. G protein-coupled bile acid receptor 1 (GPBAR1/TGR5) is a key membrane receptor for bile acids and critically regulates hepatic physiology and pathology. Given the limited direct evidence in HBV-LF, we cautiously extrapolate relevant mechanisms from chronic hepatitis B, acute liver injury and metabolic liver diseases based on shared pathological features, while noting that these mechanisms require further validation in HBV-LF models and clinical samples. We review the structure, distribution, activation and signaling pathways of GPBAR1, focusing on its protective role in HBV-LF: inhibiting excessive inflammation via NF-κB and Keap1-Nrf2 pathways, reducing hepatocyte apoptosis through mitochondrial and PI3K/Akt pathways, maintaining bile acid balance by regulating CYP7A1/CYP8A1, and improving hepatic immunity and microcirculation via NKT, CCL2/CCR2 and ET-1 axes. Abnormal GPBAR1 expression correlates with HBV-LF severity and poor prognosis. We also summarize preclinical progress of GPBAR1 agonists (e.g. INT-767, BAR501) and compare GPBAR1-targeted strategies with other GPCR therapies. This review provides a theoretical basis for mechanistic research and target identification of HBV-LF.Keywords: hepatitis b-associated liver failure, g protein-coupled bile acid receptor 1, uncontrolled inflammation, bile acid metabolism disorder, immune microenvironment imbalance