biostudies-literatureZhang YNational Natural Science Foundation of China (National Science Foundation of China)1231-1250https://www.ebi.ac.uk/biostudies/studies/S-EPMC11527992biostudies-literatureUnknown21(11)Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activiCellular & molecular immunologyRBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring.PMC115279928220195582070415, 8237182582071790, 82271797, 82341065Ren XChen HZhan ZJiang YCai BLiu XRui BDing YZhang YHuai WGao YXiang YXu SWang XWang YWang ZMa FfalseRBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring.Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activi2024-01-01T00:00:00Z2024 Nov2026-06-05T09:29:58.998Z2026-05-15T03:12:21.507ZS-EPMC115279923925178110.1038/s41423-024-01212-3