PDE4D has been reported to exhibit significantly elevated levels in the synovium of RA patients compared with OA, yet its role in RA remains underexplored. This study aimed to elucidate the role of the GRK2-PDE4D axis in FLSs and explore its potential as a therapeutic target for RA. Abundant expression of both PDE4D and GRK2 was observed in synovial tissues from both experimental arthritis animals and RA patients, with synchronized expression noted in RA patients. Global deletion of reduced disease incidence and alleviated arthritis in CIA mice. TNF-α upregulated PDE4D expression, causing abnormal FLSs activation and hyperproliferation. Inhibiting PDE4D restored cAMP levels, thereby reducing FLSs hyperproliferation, migration, and anti-apoptosis. Mechanistically, TNF-α-induced PDE4D upregulation was dependent on GRK2. Inhibition of GRK2 with CP-25, an esterification modification of paeoniflorin, reduced PDE4D expression and FLSs proliferation, while restoring cAMP levels. Both genetic deficiency and pharmacological inhibition of GRK2 decreased PDE4D expression, ameliorating arthritis severity in animal models. This is the first study to investigate the role of PDE4D in RA and to clarify that it can be regulated by GRK2. These findings suggest that targeting the GRK2-PDE4D axis represents a promising therapeutic strategy for RA.