Mast cells are heterogeneous and their function is influenced by the local microenvironment. This study shows that mast cells in the synovial tissues of patients with rheumatoid arthritis (RA) are activated via the MAS-related G protein-coupled receptor X2 (MRGPRX2), leading to increased expression of MHC class II and costimulatory molecules. In collagen-induced arthritis (CIA) mice, treatment with anti-IL-17A and cromolyn sodium significantly reduced clinical severity and bone erosion, indicating that activated mast cells contribute to RA progression and may be targeted for therapy. RA is a chronic autoimmune disease affecting 1% of the global population, characterized by synovial inflammation and joint destruction. Mast cells, innate immune cells, are involved in various inflammatory conditions, including RA. In RA, mast cells are more abundant and activated, with increased expression of MHC II and costimulatory molecules, suggesting their role in disease progression. Mast cell activation can be triggered by various receptors, including MRGPRX2, which is expressed in synovial mast cells and can be activated by ligands such as LL-37. Activation of mast cells via MRGPRX2 leads to degranulation, releasing mediators that promote inflammation and T cell responses. In RA, mast cells are activated by the synovial microenvironment, leading to increased degranulation and secretion of cytokines and chemokines that recruit and activate T cells. Mast cells can also regulate adaptive immunity by expressing MHC II and costimulatory molecules, enhancing T cell responses. In CIA mice, adoptive transfer of mast cells increased disease severity, indicating their role in promoting inflammation. Combination therapy with cromolyn sodium and anti-IL-17A reduced arthritis severity and bone erosion, suggesting that targeting mast cells can be an effective strategy for RA treatment. This study highlights the role of synovial mast cells in RA progression, mediated by MRGPRX2, and suggests that targeting mast cells could provide new therapeutic approaches for RA. The findings indicate that mast cells contribute to disease progression through degranulation and T cell activation, and that combination therapies targeting mast cells and IL-17A may be effective in treating RA.Mast cells are heterogeneous and their function is influenced by the local microenvironment. This study shows that mast cells in the synovial tissues of patients with rheumatoid arthritis (RA) are activated via the MAS-related G protein-coupled receptor X2 (MRGPRX2), leading to increased expression of MHC class II and costimulatory molecules. In collagen-induced arthritis (CIA) mice, treatment with anti-IL-17A and cromolyn sodium significantly reduced clinical severity and bone erosion, indicating that activated mast cells contribute to RA progression and may be targeted for therapy. RA is a chronic autoimmune disease affecting 1% of the global population, characterized by synovial inflammation and joint destruction. Mast cells, innate immune cells, are involved in various inflammatory conditions, including RA. In RA, mast cells are more abundant and activated, with increased expression of MHC II and costimulatory molecules, suggesting their role in disease progression. Mast cell activation can be triggered by various receptors, including MRGPRX2, which is expressed in synovial mast cells and can be activated by ligands such as LL-37. Activation of mast cells via MRGPRX2 leads to degranulation, releasing mediators that promote inflammation and T cell responses. In RA, mast cells are activated by the synovial microenvironment, leading to increased degranulation and secretion of cytokines and chemokines that recruit and activate T cells. Mast cells can also regulate adaptive immunity by expressing MHC II and costimulatory molecules, enhancing T cell responses. In CIA mice, adoptive transfer of mast cells increased disease severity, indicating their role in promoting inflammation. Combination therapy with cromolyn sodium and anti-IL-17A reduced arthritis severity and bone erosion, suggesting that targeting mast cells can be an effective strategy for RA treatment. This study highlights the role of synovial mast cells in RA progression, mediated by MRGPRX2, and suggests that targeting mast cells could provide new therapeutic approaches for RA. The findings indicate that mast cells contribute to disease progression through degranulation and T cell activation, and that combination therapies targeting mast cells and IL-17A may be effective in treating RA.