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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

Published on: June 6, 2025

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

Theodora Manolakou1, Jianyu Shen2, Sanjaykumar Boddul3

  • 1Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden. theodora.manolakou@ki.se.

Signal Transduction and Targeted Therapy
|June 10, 2026
PubMed

Insights

Researchers discovered a new way to target inflammatory T cells in autoimmune diseases. Inhibiting MTHFD1/2 with TH9619 offers a promising therapeutic strategy for rheumatoid arthritis (RA) and other inflammatory conditions.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Rheumatoid Arthritis

Background:

  • T cells drive inflammation in autoimmune diseases.
  • Current therapies have limitations in targeting pathogenic T-cell pathways for durable control.
  • Novel therapeutic targets are needed for inflammatory conditions.

Purpose of the Study:

  • Identify and characterize a novel transcriptional-metabolic axis sustaining inflammatory T-cell responses.
  • Investigate the role of NFATc1 and MTHFD2 in T-cell metabolic reprogramming in rheumatoid arthritis (RA).
  • Evaluate the therapeutic potential of MTHFD1/2 inhibition in preclinical models of arthritis.

Main Methods:

  • Identified NFATc1 binding to the MTHFD2 promoter.
  • Analyzed metabolic reprogramming in T cells from RA patients and experimental models.
  • Utilized a novel small molecule inhibitor, TH9619, targeting MTHFD1/2.
  • Performed proteomic profiling to compare TH9619 with anti-folate therapy.

Main Results:

  • NFATc1 directly regulates MTHFD2-dependent one-carbon metabolism in activated T cells.
  • TH9619 suppressed proinflammatory cytokine production and expanded regulatory T cells (Foxp3+).
  • TH9619 protected against cartilage and bone damage in vivo.
  • TH9619 induced a distinct molecular response in patient T cells compared to anti-folate therapy.

Conclusions:

  • NFATc1-mediated MTHFD2 activation is a critical regulator of T-cell-driven inflammation in RA.
  • Selective MTHFD1/2 inhibition represents a novel, mechanism-based therapeutic strategy for RA.
  • TH9619 demonstrates therapeutic potential for inflammatory diseases by targeting a key metabolic axis in T cells.

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