Matrin3 stimulates IFITM1 expression to negatively regulate hepatitis B virus RNA levels

Chronic hepatitis B virus (HBV) infection remains a major global health concern, as it is the primary contributor to liver cirrhosis and hepatocellular carcinoma. Moreover, current first-line monotherapies rarely achieve functional cures for CHB patients. Identifying novel factors or mechanisms involved in the regulation of HBV RNA levels is therefore imperative. In this study, we found that HBV infection or replication promotes the degradation of Matrin3, a pivotal regulator of the innate immune response and viral RNA levels, through interacting with the HBx-DDB1 E3 ligase enzyme complex. Functional experiments demonstrated that Matrin3 depletion significantly increased HBV RNA levels in HepG2-NTCP and primary human hepatocytes (PHHs) cell models and that this increase was dependent on IFITM1 downregulation. Mechanistically, Matrin3 binds to the promoter of IFITM1, which could promote the deposition of active histone modifications for increased expression of IFITM1, thereby activating the innate immune response and effectively reducing HBV RNA levels. Collectively, this research highlights a new way the innate immune response regulates HBV RNA levels, presenting new therapeutic avenues for treating chronic HBV infection.