<b>Hidden link in Liver-joint axis: HBV infection causes rheumatoid arthritis via TRAFD1 with unbalance of HBV X protein and trans-ferulic acid</b>

We had previously shown that liver metabolites are involved in the progression of rheumatoid arthritis (RA). However, the potential impact of hepatitis B virus (HBV) infection on RA is still unclear. In the present study, we observed a significant positive correlation between HBV infection and the risk of RA through Mendelian randomization analysis. In addition, we utilized single-cell sequencing to identify the molecular basis of fibroblast-myofibroblast transition (FMT) in the progression of HBV-induced RA (HBV-RA). The HBV-encoded protein HBx, but not HBc, HBs, or HBp, may promote FMT by upregulating TRAFD1 expression. Although HBV is a risk factor for RA, the clinical outcomes after exposure do not develop in all infected individuals. Through metabolomics analysis and weighted gene co-expression network analysis (WGCNA), we found that trans-ferulic acid (TFA) levels in the liver, joints, and peripheral blood negatively correlated with TRAFD1 expression. Furthermore, the TFAlow/HBxhi subgroup of HBV-infected individuals had a higher risk of developing RA. Interestingly, TFA treatment mitigated FMT in vitro and in vivo by downregulating TRAFD1 expression. Overall, our study demonstrates that the imbalance between TFA and HBx plays a critical role in HBV-RA onset and progression, and the liver-joint axis is a potential target for preventing the development of HBV-RA.