Hidden liver-joint axis: HBV infection causes rheumatoid arthritis via TRAFD1 with imbalance of HBV X protein and trans-ferulic acid.

Liver metabolites are involved in the progression of rheumatoid arthritis (RA), indicating a connection between the liver and joints. However, the impact and mechanism of Hepatitis B virus (HBV), a hepatotropic virus, on RA are still unclear. We investigated the correlation between HBV and RA using Mendelian randomization analysis. Single-cell transcriptome analysis was conducted to investigate changes in cell subtypes in synovial tissue of HBV-RA patients. Fibroblast-like synoviocytes (FLS) were used to create a cell model, and the transcriptome was examined to identify the key downstream molecules of FMT regulated by HBx. CIA model was constructed using HBV transgenic, HBx transgenic, and TRADF1 knockout mice to investigate the impact and mechanism of HBV on CIA. The results of our study revealed a significant positive correlation between HBV and RA. The functional studies identified a crucial role of fibroblast-myofibroblast transition (FMT) in the progression of RA. The results suggest that HBV-encoded HBx may promote FMT in RA by upregulating TRAFD1. Furthermore, trans-ferulic acid (TFA) was identified by screening for common metabolites in the liver, joints, and peripheral blood using the metabolome and WGCNA. Interestingly, we found that TFA ameliorated HBx-induced RA by suppressing TRAFD1 expression. Our study demonstrates that hidden liver-joint axis, an imbalance between TFA and HBx, plays a critical role in HBV-induced RA, which could be a potential strategy for preventing RA development.