Baricitinib Inhibits the Aggressive Phenotype of Synovial Fibroblasts in Rheumatoid Arthritis via the JAK-STAT3-EGR1 Axis.

Abstract

Synovial fibroblasts (SFs) transform into an aggressive phenotype in rheumatoid arthritis (RA), playing a significant role in sustaining synovitis and bone erosion. Baricitinib, a JAK inhibitor, has been validated as an effective treatment for RA. However, its direct inhibitory effects on RASFs remain poorly understood. The inflammatory response and aggressive behaviors (proliferation, apoptosis, migration, and invasion) of RASFs were assessed following treatment with varying concentrations of baricitinib. RNA sequencing was performed to identify differentially expressed genes and elucidate the impact of baricitinib on RASFs. The relationship between the JAK-STAT3 signaling pathway and downstream molecules (EGR1, BCL-2, MMP-2, MMP-9) was analyzed via western blotting. Collagen-induced arthritis (CIA) mice were treated with baricitinib via oral gavage or by intra-articular injection of shEGR1 to evaluate therapeutic efficacy. Baricitinib inhibited the production of inflammatory mediators in primary RASFs and reduced the progression of synovial inflammation and hyperplasia in RA patients as assessed by ultrasound. In vitro, baricitinib promoted apoptosis and inhibited the proliferation, migration, and invasion of RASFs, effects associated with decreased expression of the transcriptional regulator EGR1. In vivo, baricitinib effectively reduced arthritis scores, paw swelling, and the expression of inflammatory cytokines in the joint tissues of CIA mice. Similar therapeutic effects were observed upon inhibition of EGR1. Baricitinib inhibits the aggressive phenotype of RASFs through the JAK-STAT3-EGR1 axis, thereby contributing to the alleviation of the inflammatory response and joint destruction in RA.