Hepatic Steatosis Inhibits Hepatitis B Virus Replication by Promoting miR-122-5p-SOX4

The rising prevalence of chronic hepatitis B (CHB) and metabolic dysfunction-associated fatty liver disease (MAFLD) comorbidity necessitates a deeper understanding of their clinical interplay. Although miR-122 is a known liver-specific regulator of chronic liver diseases, its specific role in the context of CHB-MAFLD remains elucidated. In this study, serum analysis revealed that CHB-MAFLD patients exhibit significantly lower levels of HBV DNA, pgRNA, and HBsAg compared to patients with CHB alone, which correlated with elevated miR-122 expression. Through bioinformatics and molecular assays, SOX4 was identified as a direct downstream target of miR-122-5p. Utilizing an HBV-infected steatotic cell model, we observed that the comorbid state suppresses HBV replication markers-including DNA, pgRNA, HBsAg, and HBcrAg-while concurrently upregulating the miR-122-5p/SOX4 axis. Functional experiments demonstrated that miR-122-5p and SOX4 both act as inhibitors of HBV activity, as their knockdown enhanced viral replication, while their overexpression led to significant suppression. These findings suggest that the metabolic environment in CHB-MAFLD may naturally suppress HBV replication through the activation of a novel miR-122/SOX4 regulatory axis. This study highlights miR-122 as a potential therapeutic target and provides a mechanistic basis for the altered viral kinetics observed in patients with dual liver pathology. Trial Registration: Chinese Clinical Trial Registry identifier: ChiCTR2200063555.