A team from Tongji Hospital at Huazhong University of Science and Technology published a paper in Gut, a leading international journal in the field of gastroenterology and hepatology, on March 3.

The team is led by Researcher Wang Xiaojing and Professor Ning Qin from the Department of Infectious Diseases and the State Key Laboratory for the Diagnosis and Treatment of Severe Zoonotic Diseases, as well as Associate Professor Zhang Binhao's group from the Department of Hepatobiliary and Pancreatic Surgery at the hospital. Wu Wenhui, a Doctoral student, is the first author of the paper.

The team’s study reveals key mechanisms of immune imbalance in the liver in chronic hepatitis B with metabolic dysfunction-associated steatotic liver disease (MASLD), providing crucial insights into this clinical phenomenon.

Chronic hepatitis B and MASLD are the two most common types of chronic liver diseases worldwide. With lifestyle changes, an increasing number of people are affected by both diseases simultaneously. Patients with this comorbidity often exhibit a paradoxical phenomenon: a decrease in hepatitis B virus (HBV) replication levels in the blood and an increase in the serological clearance rate of hepatitis B surface antigen, yet a marked worsening of liver inflammation and fibrosis.

The research team discovered that in the livers of patients with both disease types, the innate immune signaling molecule Stimulator of Interferon Genes (STING) in macrophages exhibits abnormal accumulation and persistent activation. Under normal circumstances, once STING detects threats, such as viral invasion, it triggers an immune response, which is subsequently cleared by macrophages. However, under the dual attack of HBV and lipotoxic substances, this normal "activation-clearance" cycle is disrupted.

The key issue is the protein Rab7, which is responsible for intracellular membrane vesicle trafficking. Under healthy conditions, Rab7 functions like a "clean-up worker" within the cell, promptly assisting in transporting STING to lysosomes for degradation after triggering an immune defense. However, in the state of comorbidity, the hepatitis B virus suppresses Rab7 production, while lipotoxic substances impair Rab7's functionality. As a result, STING cannot be degraded, leading to its abnormal accumulation and persistent activation in macrophages.

In animal experiments, the research team used a Rab7 agonist, ML-098, to restore Rab7 function. The results were encouraging, as they not only significantly reduced liver inflammation and fibrosis, but also lowered HBV replication.

This research systematically reveals that the "Rab7-STING" signaling axis serves as a bridge linking metabolic disorders and immune imbalance for the first time. It provides new insights into the pathogenesis and therapeutic strategies for MASLD and hepatitis B. The research also lays an important theoretical foundation for precise immunoregulation in chronic liver diseases.

Source: Tongji Hospital, HUST