Impairment of Rab7-dependent STING degradation hampers HBV replication but accelerates disease progression in chronic hepatitis B comorbid with MASLD

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.