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

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.