Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis

  • Signal Transduct Target Ther. 2026 Jun 10;11(1):226. doi: 10.1038/s41392-026-02752-y.
Theodora Manolakou  1 ,  Jianyu Shen  #  2 ,  Sanjaykumar Boddul  #  3 ,  Martina Samiotaki  4 ,  Michail Angelos Panagias  2 ,  George Sentis  5 ,  Tarcília Aparecida Silva  6 ,  Alexandra Argyriou  3 ,  Dionysis Nikolopoulos  3 ,  Kumar Sanjiv  2 ,  Karine Chemin  3 ,  Fredrik Wermeling  3 ,  Martin Henriksson  2 ,  Ana Slipicevic  2  7 ,  Per-Johan Jakobsson  3 ,  Katerina Chatzidionysiou  3 ,  Thomas Helleday  8  9
Affiliations
  • 1. Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden. [email protected].
  • 2. Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
  • 3. Division of Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  • 4. Institute for Bioinnovation, Biomedical Sciences Research Centre "Alexander Fleming", Vari, Greece.
  • 5. Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 6. Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Federal University of Minas Gerais, Belo Horizonte, Brazil.
  • 7. One-carbon Therapeutics AB, Stockholm, Sweden.
  • 8. Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden. [email protected].
  • 9. Department of Oncology and Metabolism, Medical School, Sheffield, UK. [email protected].
  • # Contributed equally.
PMID: 42270592 DOI: 10.1038/s41392-026-02752-y
Abstract

T cells are central drivers of inflammation across autoimmune and inflammatory diseases, yet current therapies inadequately target pathogenic T-cell pathways, limiting durable disease control. Here, we identified a novel, targetable transcriptional-metabolic axis that sustains inflammatory T-cell responses, characterized by NFATc1-regulated activation of MTHFD2-dependent one-carbon metabolism. We demonstrate that NFATc1 directly binds the MTHFD2 promoter region, driving metabolic reprogramming in activated T cells from rheumatoid arthritis (RA) patients as well as in experimental arthritis models. Pharmacological inhibition of MTHFD1/2 using the novel small molecule TH9619 suppresses proinflammatory cytokine production, expands Foxp3⁺ regulatory T cells and protects against cartilage and bone damage in vivo. Proteomic profiling reveals that TH9619 elicits a distinct molecular response in patients' T cells, divergent from the currently used anti-folate therapy, particularly in inadequate responders. These findings use RA as the proving ground to establish NFATc1-mediated MTHFD2 activation as a critical regulator of sustained T-cell-driven inflammation and support selective MTHFD1/2 inhibition as a novel, mechanism-based therapeutic strategy for RA.

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