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.
