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However, the mechanisms underlying this abnormal activation in RA remain incompletely understood. In this study, we identified a significant reduction in MAPK4 expression in both RA patients and collagen-induced arthritis (CIA) mouse models, which correlates with disrupted B cell activation. Using MAPK4 knockout (KO) mice, we demonstrated that MAPK4 intrinsically promotes the differentiation of marginal zone (MZ) B cells. Loss of MAPK4 in KO mice enhances proximal BCR signaling and activates the PI3K-AKT-mTOR pathway, leading to heightened B cell proliferation. Notably, B cells from MAPK4 KO mice produce significantly higher levels of IL-6, a key pro-inflammatory cytokine in RA. Furthermore, MAPK4 KO mice exhibit impaired T cell-independent humoral immune responses. Mechanistically, MAPK4 inhibits the activation of the PI3K signaling pathway in B cells by activating the IRF4-SHIP1 pathway. Treatment with the MAPK4 agonist Vacquinol-1 enhances MZ B cell differentiation in WT mice and reduces IL-6 secretion in CIA mouse models. In summary, this study reveals the diverse roles of MAPK4 in regulating of B cell functions, with potential implications for developing therapeutic strategies for RA and related autoimmune diseases.<\/jats:p>","DOI":"10.1038\/s41419-025-07352-2","type":"journal-article","created":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T01:48:40Z","timestamp":1737856120000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["MAPK4 inhibits the early aberrant activation of B cells in rheumatoid arthritis by promoting the IRF4-SHIP1 signaling pathway"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-7758","authenticated-orcid":false,"given":"Pei","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangli","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pingping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaning","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanjuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7028-4625","authenticated-orcid":false,"given":"Chaohong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhixu","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4537-6672","authenticated-orcid":false,"given":"Zuochen","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,26]]},"reference":[{"key":"7352_CR1","first-page":"41","volume":"6","author":"AV Ebel","year":"2021","unstructured":"Ebel AV, O\u2019Dell JR. 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