Objectives <p>Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease whose pathogenesis involves the participation of numerous plasma proteins and immune cells, but their relationships are unclear. So we set out to thoroughly examine the causal link between 4907 plasma proteins and RA and to identify the involvement of 731 immunocyte phenotypes as potential mediators.</p> Methods <p>Using publicly available genome-wide association studies (GWAS) data, 5 Mendelian randomization (MR) methods (inverse variance weighted (IVW), weighted median, MR—Egger, simple mode, weighted mode) were applied for analysis, along with sensitivity analyses.</p> Results <p>27 plasma proteins and 10 immunocyte phenotypes were causally linked to RA, with most of the proteins serving as drug targets. Ephrin type-A receptor 3 (<i>EPHA3</i>) was a significant risk factor for RA (odds ratio (OR) = 1.312, 95% confidence interval (CI) [1.102, 1.562], Beta = 0.272, <i>p</i> &lt; 0.01). CD28 on CD28⁺ CD45RA⁺ CD8^br regulatory T (Treg) cells mediated the relationship between <i>EPHA3</i> levels and RA risk, with a mediation effect of 0.029 (95% CI: -0.111, 0.169), accounting for 10.7% of total effect. Moreover, Sensitivity analyses further supported the robustness of these findings.</p> Conclusion <p>Plasma proteins and immunocyte phenotypes linked to RA have been identified using MR, including <i>EPHA3</i>, which may elevate RA risk by influencing CD28 on CD28⁺ CD45RA⁺ CD8^br Treg cells. This could improve RA diagnosis and targeted therapies.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> <p><b>Key Points</b></p> <p>• <i>CD28 on CD28+ CD45RA+ CD8br Treg cells mediates the association between EPHA3 levels and RA risk, highlighting a novel pathway in RA pathogenesis.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>