GRK2-JAK1 binding represses hyperproliferation of fibroblast-like synoviocytes in rheumatoid arthritis by inhibiting STAT3 activation.

In rheumatoid arthritis (RA), dysregulated proliferation signaling in fibroblast-like synoviocytes (FLS) undermines synovial homeostasis. Attenuation of the interaction between G protein-coupled receptor kinase 2 (GRK2) and Janus kinase 1 (JAK1) facilitates activation of signal transducer and activator of transcription 3 (STAT3), thereby driving excessive cell proliferation. Nevertheless, it remains unclear whether GRK2 directly associates with JAK1 and which specific binding interfaces are responsible for restraining FLS hyperproliferation and preserving synovial equilibrium. Accordingly, this study aimed to clarify the underlying inhibitory mechanism. Our findings demonstrate that disruption of the GRK2-JAK1 interaction enhances STAT3 signaling, leading to aberrant proliferation of RA FLS. Mechanistic analyses revealed that the C-terminal region of GRK2 directly interacts with the Src homology 2 (SH2) domain of JAK1, thereby suppressing STAT3 activation. This inhibitory interaction critically depends on the arginine residues R466 and R506 within the JAK1 SH2 domain. Notably, pharmacological inhibition of GRK2 strengthened the GRK2-JAK1 association and attenuated STAT3 activation in both in vitro and in vivo models. As a consequence, excessive FLS proliferation and the expression of pro-inflammatory and lipid mediators were reduced to near-physiological levels, ultimately restoring synovial homeostasis through a mechanism distinct from that of conventional JAK inhibitors. Collectively, these results uncover a previously unrecognized negative regulatory axis involving GRK2 and JAK1 and highlight the essential role of GRK2 in controlling FLS proliferation and synovial homeostasis in RA, suggesting a promising therapeutic strategy that may avoid the adverse effects associated with direct JAK inhibition.