This study reports that the mitochondrial aminotransferase BCAT2 is upregulated in synovial macrophages from individuals with active rheumatoid arthritis (RA) and that this upregulation functionally connects branched-chain amino acid (BCAA) catabolism to local inflammation. Clinical and molecular analyses showed systemic depletion of BCAAs in active disease and accumulation of branched-chain ketoacids in synovial tissue, supporting enhanced local BCAA catabolic flux. Histological and multi-omics data localized elevated BCAT2 expression specifically to interferon-responsive macrophage populations in inflamed synovia.
Single-cell RNA sequencing and histological profiling identified a population of synovial macrophages with an interferon-response signature that expressed high levels of BCAT2. The authors report that interferon-γ induced BCAT2 transcription in RA synovial macrophages and that this induction was mediated by the transcription factor IRF1, linking canonical interferon signaling to metabolic reprogramming toward BCAA catabolism in these cells.
Functional studies in human monocyte-derived macrophages showed that BCAT2-dependent catabolism of BCAAs contributed to a proinflammatory state. When BCAT2 activity supported BCAA catabolism, macrophages displayed increased production of inflammatory cytokines. The metabolic phenotype observed in patient tissues—systemic BCAA depletion together with synovial branched-chain ketoacid accumulation—corresponds to enhanced BCAT2-mediated flux in the inflamed joint environment.
Mechanistically, BCAT2-driven BCAA catabolism elevated mitochondrial ROS levels in macrophages. Elevated mitochondrial ROS, in turn, suppressed the activity of the tyrosine phosphatase SHP-1, resulting in prolonged phosphorylation of STAT1 and STAT2. Sustained STAT phosphorylation amplified interferon-stimulated transcriptional programs and supported continued inflammatory cytokine production. Thus, the pathway links metabolic activity (BCAA catabolism) to redox modulation (mitochondrial ROS), phosphatase inhibition (SHP-1) and prolonged interferon signaling in macrophages.
To test the in vivo relevance, the authors used a myeloid-specific Bcat2 deletion in mice and assessed disease in the collagen antibody-induced arthritis model. Myeloid Bcat2 deficiency ameliorated arthritis severity and reduced activation of interferon-stimulated genes (ISGs) in myeloid cells. These genetic data support a causal role for myeloid BCAT2 in sustaining interferon-driven macrophage activation and in promoting inflammatory arthritis in this experimental model.
The authors evaluated pharmacological targeting of the BCAT2-linked pathway and report that treatment with telmisartan suppressed persistent arthritis in methotrexate-treated mice. Telmisartan treatment limited BCAT2-associated macrophage activation in the models used, indicating a possible therapeutic avenue for targeting this metabolic–inflammatory axis in autoimmune arthritis.
The study integrates multi-omics and scRNA-seq datasets. Previously published scRNA-seq datasets analyzed are available at the National Genomics Data Center (BioProject PRJCA013514) and EMBL-EBI (E-MTAB-8322). scRNA-seq datasets generated in this study from synovial tissue macrophages (STMs) of patients with RA were deposited in the Genome Sequence Archive for Human (HRA016381) with appropriate permissions. Mouse scRNA-seq datasets from ankle and bone marrow cells were deposited (CRA040312). Mass spectrometry proteomics data were deposited in OMIX011263. The computational pipelines and source code for scRNA-seq analyses are publicly available on GitHub at https://github.com/drxiaohuimeng/NI-Rheumatoid-Arthritis-Single-Cell-Analysis. Source data are provided with the paper; other supporting data are available from the corresponding authors upon reasonable request.
Figures referenced in the article summarize key findings: upregulation of BCAT2 in synovial macrophages (Fig. 1); IFN-associated synovial macrophages and BCAT2 expression (Fig. 2); BCAT2-dependent BCAA catabolism sustaining macrophage activation (Fig. 3); BCAT2 promotion of STAT signaling through mitochondrial ROS (Fig. 4); myeloid Bcat2 deficiency ameliorating inflammatory arthritis (Fig. 5); and telmisartan limiting BCAT2-linked macrophage activation (Fig. 6).
Conclusions
Using patient samples, in vitro human macrophage experiments and mouse genetic and pharmacological models, the study identifies a mechanism in which BCAT2-dependent BCAA catabolism sustains interferon-driven macrophage activation via mitochondrial ROS–mediated suppression of SHP-1, leading to prolonged STAT1/STAT2 signaling and persistent inflammatory cytokine production. The pathway is presented as a potentially targetable metabolic regulator of chronic inflammation in autoimmune arthritis.