AUTHOR=Yang Fan , Hu Feng , Song Hongxiao , Li Tie , Xu Fengchao , Xu Jing , Wang Le , Wang Fei , Zhu Yujia , Huang Mian , Gao Yanli , Rao Min , Ma Haichun , Tan Guangyun 

TITLE=Cholesterol metabolism regulator SREBP2 inhibits HBV replication via suppression of HBx nuclear translocation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1519639

DOI=10.3389/fimmu.2024.1519639

ISSN=1664-3224

ABSTRACT=The intricate link between cholesterol metabolism and host immune responses is well recognized, but the specific mechanisms by which cholesterol biosynthesis influences hepatitis B virus (HBV) replication remain unclear. In this study, we show that SREBP2, a key regulator of cholesterol metabolism, inhibits HBV replication by interacting directly with the HBx protein, thereby preventing its nuclear translocation. We also found that inhibiting the ER-to-Golgi transport of the SCAP-SREBP2 complex or blocking SREBP2 maturation significantly enhances HBV suppression. Notably, we demonstrate that the C-terminal domain (CTD) of SREBP2, rather than its N-terminal domain (NTD), mediates this inhibition by interacting with HBx and promoting its extracellular secretion, thus reducing nuclear HBx accumulation. These findings reveal a novel regulatory pathway that links cholesterol metabolism to HBV replication via SREBP2-mediated control of HBx localization. This insight provides a potential basis for new therapeutic strategies against HBV infection, addressing an important global health issue.