PYHIN proteins: guardians or contributors to hepatitis B virus pathogenesis?

Human pyrin and HIN domain (PYHIN) family proteins play central roles in the host defense against viral infection. These PYHIN proteins, including IFI16, AIM2, MNDA and PYHIN1, mainly function as intracellular DNA sensors. Among them, IFI16 is supported by the most robust mechanistic evidence, including direct binding to hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in the nucleus and subsequent suppression of viral transcription. They recognize HBV DNA in different cellular substructures, triggering innate immune responses and interfering with steps of the viral life cycle. This article reviews the latest research progress of the PYHIN protein in HBV infection, and summarizes its immunoregulatory function and its role in the disease progression. We focus on the important question of the dual antiviral and pro-damage functions of PYHIN. On one hand, PYHIN has the ability to sense HBV DNA and inhibit the replication of the HBV. On the other hand, the host response mediated by PYHIN may also promote chronic inflammation, genomic instability and tumor formation. Furthermore, we collated the mechanism by which HBV evaded inflammasome activation by suppressing PYHIN expression through HBx. Here, we have emphasized the necessity of conducting in-depth mechanism research to clarify the role of the PYHIN family proteins in HBV infection contexts, and proposed the feasibility of implementing precise targeted immunotherapy based on the functions of PYHIN, aiming to provide strategies for achieving hepatitis B cure.