FOXC1-ATP7A Axis Activates PI3K/AKT Signaling to Suppress Cuproptosis and Drive Fibroblast Pathogenesis in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. The underlying molecular mechanisms remain incompletely defined. Transcriptomic data of RA and normal synovial samples (GSE89408) were analyzed to identify the differentially expressed genes (DEGs). WGCNA, GO/KEGG enrichment, and PPI analysis were performed on the DEGs to screen for hub genes involved in RA progression. The proliferation, apoptosis, migration, and invasion of the MH7A fibroblast-like synoviocytes were evaluated through routine functional assays. QRT-PCR and Western blotting were conducted for molecular validation. Bioinformatics analyses identified FOXC1 as a hub transcription factor in RA and confirmed its co-expression with ATP7A. FOXC1 was markedly upregulated in RA tissues and fibroblasts, where it enhanced ATP7A expression. Overexpression of FOXC1 or ATP7A promoted the proliferation, invasion, and migration of RA fibroblasts while inhibiting apoptosis. Knockdown of ATP7A abrogated the effects of FOXC1. Mechanistically, the FOXC1-ATP7A axis activated PI3K/AKT/mTOR signaling and reduced markers of cuproptosis in the MH7A cells, suggesting an essential role in maintaining fibroblast pathogenicity. FOXC1 is a novel upstream regulator of ATP7A in synovial fibroblasts, and the FOXC1/ATP7A/PI3K/AKT pathway mediates RA pathogenesis by activating the synovial fibroblasts and suppressing cuproptosis. Targeting this axis may provide new therapeutic opportunities for RA.