2. Academic Validation
  3. Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy

Targeting the Mapk13-Tcf1-Slc7a5 Axis via One-Carbon Metabolic Regulation to Prevent Chronic Allograft Vasculopathy

  • Adv Sci (Weinh). 2026 Mar;13(17):e20815. doi: 10.1002/advs.202520815.
Wang Yi 1 2 3,  Di Wu 4,  Jing Liu 1 2 3,  Shi Chen 1 2 3,  Liu Song 1 2 3,  Bin Xie 1 2 3,  Aini Xie 1 2 3,  Peixiang Lan 1 2 3,  Zhishui Chen 1 2 3 5
Affiliations

Affiliations

  • 1 Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
  • 3 NHC Key Laboratory of Organ Transplantation, Wuhan, Hubei, China.
  • 4 Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 5 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, China.
PMID: 41538426 DOI: 10.1002/advs.202520815
Abstract

Chronic allograft vasculopathy (CAV) is driven in part by stem-like CD4+ T cells, but how these cells sustain their progenitor programs during chronic rejection remains unclear. Here, a metabolic-epigenetic axis is identified in which MAPK13 phosphorylates Tcf1 at T289, enabling Tcf1 to activate the Amino acid Transporter Slc7a5 and enhance methionine uptake. This rewires one-carbon metabolism and increases H3K4me3 enrichment at the Tcf7 locus, thereby maintaining stem-like CD4+ T cells within rejecting grafts. Disruption of this circuit-via genetic deletion of MAPK13 or Slc7a5, or through dietary methionine restriction-reduces Tcf1+ CD4+ T cell stemness and prevents CAV in mouse models. These findings reveal the Mapk13-Tcf1-Slc7a5 axis as a critical metabolic dependency of pathogenic T cells and highlight one-carbon metabolism as a promising target to promote long-term graft survival.

Keywords

TCF1; chronic allograft vasculopathy; methionine restriction; one‐carbon metabolism; stem cell‐like T cells.

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