Authors
Xiaohui Meng, Haihui Han, Wulin You, Pengfei Xin, Ya Ju, Liangyu Cai, Lamei Zhou, Sheng Zhong, Zhuoyi Hu, Zhiyu Chen, Wenlei Qin, Yanhao Ge, Wei Yao, Lianbo Xiao, Yafeng Zhang
Published in
Nature immunology. Jul 31, 2026. Epub Jul 31, 2026.
Abstract
The mechanisms sustaining chronic inflammation in rheumatoid arthritis (RA) remain incompletely understood. Here we show that branched-chain amino acid (BCAA) catabolism, mediated by the mitochondrial enzyme BCAT2, sustained interferon-driven macrophage activation in autoimmune arthritis. Multi-omics and histological analyses of individuals with active RA or sustained remission revealed that active disease was associated with systemic BCAA depletion, synovial branched-chain ketoacid accumulation and elevated BCAT2 expression in interferon-responsive synovial macrophages. Mechanistically, interferon-γ induced BCAT2 transcription through the transcription factor IRF1 in RA synovial macrophages. In human monocyte-derived macrophages, BCAT2-dependent BCAA catabolism elevated mitochondrial reactive oxygen species, which in turn restrained SHP-1 activity, prolonged STAT1 and STAT2 phosphorylation and drove inflammatory cytokine production. Furthermore, myeloid-specific deletion of Bcat2 ameliorated collagen antibody-induced arthritis in mice. Pharmacological targeting of this pathway with telmisartan suppressed persistent arthritis in methotrexate-treated mice. Together, our findings identified BCAT2-dependent amino acid catabolism as a potentially targetable metabolic pathway in autoimmune arthritis.
PMID:
42538461
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.
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