Authors
Theodora Manolakou, Jianyu Shen, Sanjaykumar Boddul, Martina Samiotaki, Michail Angelos Panagias, George Sentis, Tarcília Aparecida Silva, Alexandra Argyriou, Dionysis Nikolopoulos, Kumar Sanjiv, Karine Chemin, Fredrik Wermeling, Martin Henriksson, Ana Slipicevic, Per-Johan Jakobsson, Katerina Chatzidionysiou, Thomas Helleday
Published in
Signal transduction and targeted therapy. Volume 11. Issue 1. Jun 10, 2026. Epub Jun 10, 2026.
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.
PMID:
42270592
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.
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