Hepatitis B Virus Increases SphK1-S1P Synthesis by Promoting the Availability of the Transcription Factor USF1.

Hepatitis B virus (HBV) is the most common chronic viral infection globally, affecting ∼360 million people and causing about 1 million deaths annually due to end-stage liver disease or hepatocellular carcinoma. Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)-sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2-sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1-S1P. These findings suggest that the SphK1-S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury.