This study investigates the role of mast cells in the progression of rheumatoid arthritis (RA). Mast cells, known for their heterogeneous phenotypes and functions, are influenced by the local microenvironment. The research shows that mast cells in the synovial tissues of RA patients are activated through MAS-related G protein-coupled receptor X2 (MRGPRX2), leading to increased degranulation and upregulation of MHC class II and costimulatory molecules. In collagen-induced arthritis (CIA) mice, treatment with anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, significantly reduced clinical severity and bone erosion. The findings suggest that synovial microenvironment-influenced mast cells contribute to RA progression and may provide a new therapeutic target for RA. The study also highlights the importance of MRGPRX2 in mast cell activation and the potential of combining cromolyn sodium with anti-IL-17A therapy to improve disease outcomes.This study investigates the role of mast cells in the progression of rheumatoid arthritis (RA). Mast cells, known for their heterogeneous phenotypes and functions, are influenced by the local microenvironment. The research shows that mast cells in the synovial tissues of RA patients are activated through MAS-related G protein-coupled receptor X2 (MRGPRX2), leading to increased degranulation and upregulation of MHC class II and costimulatory molecules. In collagen-induced arthritis (CIA) mice, treatment with anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, significantly reduced clinical severity and bone erosion. The findings suggest that synovial microenvironment-influenced mast cells contribute to RA progression and may provide a new therapeutic target for RA. The study also highlights the importance of MRGPRX2 in mast cell activation and the potential of combining cromolyn sodium with anti-IL-17A therapy to improve disease outcomes.