LncRNA RNA XIST binding to GATA1 contributes to rheumatoid arthritis through its effects on proliferation of synovial fibroblasts and angiogenesis via regulation of CCN6.

This study explored the role of the long non-coding RNA (lncRNA) XIST (X-inactive specific transcript) as a driver of RA pathogenesis, with a particular focus on the ability of this lncRNA to interact with GATA1 and CCN6. The GSE83147and GSE181614 datasets were downloaded for analysis. XIST and CCN6 expression were assessed in synovial fibroblasts (SFs) and in both normal cartilage samples and those from RA patients, with the relationship between XIST and CCN6 additionally being examined. XIST and CCN6 were respectively knocked down or overexpressed in SFs to establish their regulatory roles in these cells in the context of RA. Further studies of the regulatory interplay between XIST, GATA1, and CCN6 were then performed through RNA immunoprecipitation, RNA pull-down, gain-of-function, loss-of-function, and luciferase reporter assays. In addition, RA model rats were established and used to measure the production of TNF-α, IL-6, and IL-8 and to subject tissues from these animals to histopathological examination. RA patient synovial tissues and SFs exhibited XIST and CCN6 upregulation. The knockdown of XIST suppressed SF migratory, proliferative, invasive, and angiogenic activity, while CCN6 knockdown partially reversed the ability of XIST to influence these phenotypic outcomes in vitro and in vivo. XIST bound to GATA1 within SFs, thus promoting enhanced CCN6 transcription. Knocking down XIST alleviated RA-related pathological damage, synovial injury, and inflammatory response induction in rats. The binding of XIST to GATA1 leads to CCN6 upregulation, driving RA pathogenesis by altering SF proliferation and angiogenic activity, suggesting that this pathway may represent a viable target for therapeutic intervention.