Plexin C1 promotes synovial aggression and inflammation through STAT3-dependent Cyclin D1 activation in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, in which fibroblast-like synoviocytes (FLS) play a central pathogenic role. However, the molecular regulators driving FLS activation remain incompletely defined. Here, we identify Plexin C1 (PLXNC1) as a previously underappreciated regulator of RA pathogenesis. PLXNC1 was significantly upregulated in RA synovial tissues and FLS and positively correlated with disease activity. Functional assays demonstrated that PLXNC1 knockdown markedly suppressed FLS migration, invasion, proliferation, cell cycle progression, and inflammatory cytokine expression, without significantly affecting apoptosis. Mechanistically, bioinformatics analysis and experimental validation identified CCND1/ Cyclin D1 as a critical downstream effector of Plexin C1. PLXNC1 silencing reduced CCND1 expression, whereas Cyclin D1 overexpression rescued the impaired aggressive phenotype of FLS caused by PLXNC1 knockdown. Further mechanistic investigation revealed that Plexin C1 regulates CCND1 transcription through activation of STAT3 phosphorylation at Tyr705, establishing a PLXNC1/STAT3/CCND1 signaling axis. In vivo, intra-articular delivery of PLXNC1-targeting adenovirus significantly alleviated synovial inflammation, cartilage destruction, and bone erosion in a collagen-induced arthritis (CIA) model. Collectively, these findings identify Plexin C1 as a regulator of pathogenic FLS behavior, and suggest that targeting the PLXNC1/STAT3/CCND1 axis may represent a promising therapeutic strategy for RA.