2. Academic Validation
  3. Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis

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

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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