Peiyu Liu, Jingtao Zhang, Jingrong Wang, Runze Li, Ruimin Tian, Shiyuan Wang, Yingjie Zhang, Zhengmin Chen, Yao Peng, Yuan Liu, Fujie Cai, Yiyuan Wang, Yuqing Chen, Xizi He, Yu Lai, Qingyang Zhao, Jinfang Wang, Chunye He, Xian Xiao, Cuifen Zhang, Yang Liao, Qingming Ke, Yulian Chen, Danli Chen, Biyi Pang, Jiayan Lu, Min Zhou, Yani Pi, Yishen Liu, Haiqiong Zhu, Beibei Dong, Xiaoman Chen, Haofeng Zeng, Jiayi Huang, Yufei Song, Junwen Gong, Zhiyu Chen, Minqi Quan, Huating Hu, Rongrong Li, Jiaqi Wu, Jiaqi Zhang, Ziqin Ye, Liang Liu, Hudan Pan
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.