<p>Rheumatoid arthritis (RA) has made significant progress in the treatment zone passing on from traditional disease-modifying anti-rheumatic drugs (DMARDs) to novel biologics and targeted synthetic agents with the goal of individualized therapy regimens. However, these novel biological treatments necessitate careful evaluation due to their effectiveness and side effects. In recent decades, new therapy methods have emerged to understand the underlying causes of RA better, highlighting the need to update current treatments. It is observed that in the context of RA pathophysiology, there was prolonged stimulation of the human prostaglandin E2 receptor 4 (EP4) by prostaglandin E2(PGE2), and also M2 macrophage polarization is promoted by PGE2 through the cyclic adenosine monophosphate - response element binding protein (cAMP-CREB) pathway which leads to the recruitment of G protein–coupled receptor kinase 2 (GRK2) to the membrane and, as a result, there is under expression of membrane-associated EP4. This review emphasizes the significant role of GRK2 in the pathophysiology of RA by regulating the PGE2-EP4 pathway, fibroblast-like synoviocyte (FLS) proliferation, and peroxisome proliferator–activated receptor gamma (PPAR γ) - Tyr473(Flt-1 transcription). Recent research has highlighted the regulatory function of PGE2 and its receptor, EP4, in initiating RA pathogenesis. Additionally, it discusses the mechanism of action supported by current literature, existing therapies, and novel drugs undergoing pre-clinical and clinical trials, which could help future researchers explore them in treating this ancient autoimmune disorder RA.</p> Graphical Abstract <p>GRK2 and PGE2 regulation in RA: mechanisms and therapeutic potentials. Abbreviations: RA, rheumatoid arthritis; GRK2, G protein–coupled receptor kinase 2; PGE2, prostaglandin E2; YAP, Yes-associated protein; SAV1, salvador homolog 1; CP-25, paeoniflorin-6ʹ-O-benzene sulfonate; FLS, fibroblast-like synoviocytes; EP4, human prostaglandin E2 receptor 4; MDMs, monocyte-derived macrophages; Flt-1+/VEGFR-1, vascular endothelial growth factor receptor 1; PPARγ, peroxisome proliferator–activated receptor gamma; LBD, ligand-binding domain; KD, kinase domain; RH domain, RGS homology domain; PH domain, Pleckstrin homology domain</p> <p></p>