DMp39

DMp39 is a novel decoy peptide designed to target the interaction between mitochondrial dihydrolipoyl transacetylase (DLAT) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). In chemoresistant cancer cells, DLAT binds to and acetylates MTHFD2 at lysine 44, which activates mitochondrial tetrahydrofolate metabolism and increases 10-formyl-tetrahydrofolate levels. This metabolic rewiring induces the expression of mitochondrial-encoded cytochrome c oxidase II (MT-CO2) and enhances mitochondrial oxidative capacity, supporting cell survival under chemotherapeutic stress. DMp39 specifically disrupts this DLAT-MTHFD2 signaling axis, thereby inhibiting the metabolic adaptations that lead to resistance. Preclinical studies in patient-derived xenograft models have demonstrated that DMp39 can restore sensitivity to chemotherapy, offering a potential therapeutic strategy for patients with cancers refractory to standard chemotherapy or chemoimmunotherapy.