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Impairment of Rab7-dependent STING degradation hampers HBV replication but accelerates disease progression in chronic
Wenhui Wu1, Qiang Gao1, Suping Hai1
1Department of Infectious Diseases, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China.
Background:
Concomitant metabolic dysfunction-associated steatotic liver disease (MASLD) is prevalent in patients with chronic hepatitis B (CHB), yet its impact on liver-related outcomes remains controversial. Although the stimulator of interferon genes (STING) pathway is pivotal in innate immunity, its involvement in CHB-MASLD comorbidity is undefined.
Objective:
We aimed to elucidate the role and mechanism of macrophage STING in CHB-MASLD comorbidity.
Design:
Human and mouse liver tissues were used to assess STING expression levels. Myeloid-specific STING knockout and hepatocyte-specific STING knock-in mice were used to explore the effects of STING in comorbidity. Tohoku Hospital Pediatrics (THP)-1 and HepG2.2.15/HepG2-NTCP co-cultured cells were stimulated with palmitic acid (PA) for 12 hours in vitro for mechanism research. Markers for STING, autophagy and endoplasmic reticulum stress (ERS) were assessed using western blot analysis, immunohistochemistry and immunofluorescence assays. The liver organoids were used for validation.
Results:
CHB-MASLD comorbidity in mice decreased HBV replication but accelerated liver inflammation and fibrosis, linked to aberrant STING upregulation in macrophages. HBV synergised with lipotoxicity to disrupt Rab7 expression and function in macrophages, impairing STING degradation via autophagic-lysosomal and endosomal-lysosomal pathways. Pathological STING accumulation had dual effects: cytosolic STING enhanced antiviral activity (TANK-binding kinase 1-interferon regulatory factor 3-interferon beta) and promoted inflammation (nuclear factor kappa-B/NOD-like receptor family pyrin domain-containing 3 (NLRP3)). Extracellular vesicles transported STING to hepatocytes, triggering ERS (PKR-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP)), further activating NLRP3 and exacerbating injury. Therapeutically, restoring Rab7 facilitated STING degradation, attenuating pathology.
Conclusions:
In CHB-MASLD comorbidity, impaired Rab7 function leads to aberrant STING accumulation in macrophages, suppressing HBV replication but paradoxically accelerating liver disease progression. Targeting Rab7 to degrade excessive STING represents a novel therapeutic strategy.
Insights
In chronic hepatitis B with metabolic dysfunction-associated steatotic liver disease (CHB-MASLD), macrophage STING accumulates due to impaired Rab7, worsening liver disease. Restoring Rab7 function offers a new therapeutic approach.
Area of Science:
- Hepatology
- Immunology
- Infectious Diseases
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in chronic hepatitis B (CHB) patients, but its combined effect on liver outcomes is unclear.
- The role of the stimulator of interferon genes (STING) pathway in CHB-MASLD comorbidity is unknown.
Purpose of the Study:
- To investigate the function and mechanism of macrophage STING in CHB-MASLD comorbidity.
Main Methods:
- Assessed STING levels in human and mouse liver tissues.
- Utilized myeloid-specific STING knockout and hepatocyte-specific STING knock-in mice.
- Examined STING, autophagy, and endoplasmic reticulum stress markers in co-cultured cells and liver organoids.
Main Results:
- CHB-MASLD accelerated liver inflammation and fibrosis, linked to increased macrophage STING.
- HBV and lipotoxicity impaired macrophage Rab7, hindering STING degradation and leading to its accumulation.
- Accumulated STING promoted inflammation and endoplasmic reticulum stress in hepatocytes via extracellular vesicles, worsening liver injury.
Conclusions:
- Impaired Rab7 in CHB-MASLD causes aberrant macrophage STING accumulation, paradoxically accelerating liver disease despite suppressing HBV replication.
- Targeting Rab7 to enhance STING degradation presents a novel therapeutic strategy for CHB-MASLD.
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