Background/Purpose: Rapidly proliferating cells fuel their increased nucleotide demand by boosting one-carbon metabolism, associated with the survival of pathogenic proliferative cells and the release of T cell immunogenic responses in T-cell driven diseases. Recent studies have shown that selective inhibition of one-carbon metabolism components has therapeutic potential in cancer and autoimmune models in vivo. This study aims to investigate the role of one-carbon metabolism in rheumatoid arthritis (RA) pathogenesis, evaluate its reprogramming as a therapeutic strategy, and explore its components as potential biomarkers for response to current RA therapies.

Methods: Bioinformatic analysis of publicly available transcriptomic data from immune cell populations of the blood and synovial fluid of treatment-naive RA patients and healthy controls to reveal associations of one-carbon metabolism-related molecular signature with specific immune cell populations. Additional analysis of whole blood microarrays from RA patients resistant to current therapies to reveal biomarkers for drug response. Immunofluorescence microscopy on patient-derived T cells to investigate the differential expression of one-carbon metabolism components before and post standard-of-care treatments. Ex vivo studies with exposure of activated patient-derived T cells to one-carbon metabolism inhibitors or methotrexate, and investigation of immune responses and the proteome. In vivo studies with exposure of a murine model of inflammatory arthritis to selective inhibitors of one-carbon metabolism components to assess the therapeutic potential of the novel targets.

Results: Transcriptomic analysis and immunofluorescence studies revealed that MTHFD2 and MTHFD1 one-carbon metabolism components are upregulated primarily in T cell populations of RA patients compared to healthy controls. Inadequate-responder RA patients to current standard-of-care show dysregulated MTHFD1/2 expression. Ex vivo MTHFD1/2 inhibition with novel compounds alleviated T cell immunogenicity in RA patients, including inadequately-responders to methotrexate, while the proteomic analysis revealed unique signature of MTHFD1/2i-treated cells compared to the MTX-treated. Arthritic mice treated with MTHFD1/2i exhibit increased levels of T regulatory cells and reduced joint inflammation.

Conclusion: MTHFD1 and MTHFD2 appear to be deregulated in RA patients, including those who do not respond to standard treatments. Inhibition of these targets may reduce T cell immunogenicity and result in distinct proteomic changes compared to methotrexate. Additionally, MTHFD1/2 inhibition shows potential in improving arthritis in an experimental in vivo model. These findings suggest that selective targeting of one-carbon metabolism components could be explored as a novel therapeutic strategy for RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-targeting-of-one-carbon-metabolism-to-combat-rheumatoid-arthritis/