Patient-Derived Transcriptomics Reveals Distinct IFNγ-Associated Myeloid States and Mitochondrial Complex I Programs in Rheumatoid Arthritis and Osteoarthritis.

Background/Objectives: Macrophages are key contributors to the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA), but their disease-associated immunometabolic states remain incompletely understood. Methods: Here, we comparatively analyzed patient-derived transcriptomic data from synovial tissues and synovial macrophages in RA and OA. Results: RA synovial tissues showed stronger interferon-γ (IFNγ)-associated signatures and reduced mitochondrial Complex I-related programs compared with OA. Similar reductions in oxidative phosphorylation, mitochondrial translation, and Complex I-related transcription were observed in synovial fluid-derived RA macrophages relative to control macrophages. In an independent dataset of synovial tissue-derived OA macrophages, inflammatory-like OA macrophages exhibited concurrent enrichment of glycolytic and oxidative metabolic programs. Bulk RNA-seq analysis of synovial monocytes within a common study framework further showed that reduced mitochondrial translation and Complex I-related programs were preferentially associated with leukocyte-rich inflammatory RA. At single-cell resolution, IFN-responsive monocytes enriched in leukocyte-rich RA showed reduced transcriptional representation of both nuclear- and mtDNA-encoded Complex I components. Conclusions: Collectively, these findings link an IFN-responsive inflammatory myeloid state in RA with coordinated suppression of mitochondrial translation and Complex I-related transcription, suggesting a transcriptional state that may increase susceptibility to mitochondrial Complex I dysfunction during persistent inflammation.