Silent sabotage: How hepatitis B virus-miR-3 disarms innate immunity through cGAS-STING suppression

In this editorial, we comment on the article by Xu et al published in the recent issue of the World Journal of Hepatology. The hepatitis B virus (HBV) has evolved sophisticated mechanisms to evade host innate immunity, a hallmark of its persistent infections. This study highlights a pivotal role for HBV-encoded microRNA, specifically HBV-miR-3, in undermining the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING)-IFN signaling axis. This pathway is critical for recognizing viral DNA and subsequent production of type I interferons, key antiviral cytokines. HBV-miR-3 achieves this immune evasion by directly downregulating the expression of cGAS, an essential DNA sensor, and STING, its downstream adaptor. By silencing these components, HBV-miR-3 disrupts the activation of downstream interferon regulatory factor 3 and Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells transcription factors, thereby blunting interferon beta production and antiviral gene expression. This strategy allows HBV to persist in hepatocytes by dampening innate immune responses and contributes to immune tolerance, fostering chronic infection. Understanding the role of HBV-miR-3 provides novel insights into HBV pathogenesis and identifies potential therapeutic targets to restore antiviral immunity. Targeting HBV-miR-3 or reactivating the cGAS-STING-IFN pathway could offer promising strategies to counteract HBV immune evasion and resolve chronic infection.