Natural small molecule bergapten ameliorates rheumatoid arthritis by targeting STAT3

Rheumatoid arthritis (RA) is a severe and chronic inflammatory disease that currently has almost no cure. Here, we report a natural small molecule bergapten (BG) as a promising treatment for RA. Firstly, our results show BG treatment significantly inhibits RA in collagen-induced arthritis (CIA) rats. Then, through single-cell RNA sequencing (scRNA-seq) analysis of synovium tissue of CIA rats, we find that the proportion of inflammation-related cells, including fibroblast-like synoviocytes (FLSs) and macrophages, are significantly reduced following BG treatment. Additionally, BG markedly blocks the interaction between macrophages and FLSs, which further decreases the inflammation in synovium tissue of CIA rats. Mechanistically, BG exerts its anti-inflammatory effects, at least partially, by binding to STAT3, a key regulator of inflammation, thereby inhibiting STAT3 phosphorylation and activation, which leads to the suppression of the STAT3 signaling pathway in both macrophages and FLSs. Our study provides a promising drug candidate for the treatment of RA and also suggests the potential of BG in treating other diseases linked to dysregulated STAT3.