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FOXO4-DRI – Key Research Facts Full name: FOXO4 D-Retro-Inverso peptide (FOXO4-DRI) Classification: Cell-penetrating senolytic peptide — FOXO4/p53 protein-protein interaction inhibitor Design: D-retro-inverso isoform of FOXO4’s p53-binding domain — reversed sequence with all D-amino acids Binding target: p53 transactivation domain 2 (TAD2) — displaces FOXO4 from the FOXO4-p53 complex Mechanism: FOXO4-DRI binds p53 TAD2 → p53 nuclear exclusion → p53 mitochondrial translocation → BAX activation → caspase-3 cleavage → senescent cell-selective apoptosis Selectivity basis: FOXO4 is upregulated in senescent cells but expressed at low levels in most non-senescent adult cells — selectivity is mechanistically conferred D-amino acid advantage: Proteolytic stability — resistant to intracellular peptidases that would rapidly degrade equivalent L-amino acid sequences Structural characterisation: NMR structural models of FOXO4-DRI/p53TAD2 complex resolved (Nature Communications, 2025) — confirms disordered-to-ordered transition upon binding Research cell types studied: IMR90 fibroblasts, TM3 Leydig cells, endothelial cells, chondrocytes, keloid fibroblasts, HCT116 cancer cells In vitro working concentration: 25 µM used in multiple published studies for senescent cell apoptosis induction What Does FOXO4-DRI Do in Research
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