Sinomenine modulates an MGAT3-associated B-cell IgG N-glycosylation pathway linked to macrophage FcγRIII/CD16-related signaling in rheumatoid arthritis.

Rheumatoid arthritis (RA) is sustained not only by cytokine-driven inflammation but also by immune complex-mediated Fcγ receptor activation. Although IgG Fc N-glycosylation at Asn297 critically regulates Fcγ receptor engagement, the upstream enzymatic mechanisms shaping pathogenic IgG Fc glycoforms in RA and their pharmacological tractability remain unclear. Here, B-cell MGAT3 was investigated as a glycosyltransferase associated with IgG N-glycan remodeling and macrophage FcγRIII/CD16-related inflammatory signaling. MGAT3 was reduced in RA peripheral blood and synovial tissues, and low MGAT3 was associated with decreased PHA-E-reactive bisecting GlcNAc-related signals, altered IgG N-glycan profiles, and enhanced FcγRIII/CD16-related phosphotyrosine/Syk/NF-κB signaling with increased TNF-α, IL-6, and IL-1β. Mechanistically, sinomenine (SIN) bound to MGAT3, as supported by docking, MST, SPR, and CETSA, and stabilized MGAT3 by reducing ubiquitination-dependent degradation. SIN increased MGAT3-associated bisecting GlcNAc-related glycan signals, suppressed macrophage FcγRIII/CD16-related signaling, and alleviated collagen-induced arthritis. MGAT3 knockdown weakened the therapeutic effect of SIN, whereas receptor blockade and MGAT3 re-expression experiments further supported the involvement of MGAT3-associated FcγR signaling. These findings support an MGAT3-centered B-cell IgG glycosylation pathway linked to macrophage inflammatory activation and suggest SIN-mediated MGAT3 stabilization as a potential glycoimmunomodulatory strategy for RA.