FOXO4-DRI (Forkhead Box O4 - D-Retro-Inverso) is a synthetic cell-penetrating senolytic peptide with an approximate molecular weight of 5400 g/mol. Its structure consists of a D-retro-inverso (DRI) modified segment derived from the forkhead domain of the FOXO4 transcription factor, fused to a cationic cell-penetrating peptide (CPP) sequence. The D-retro-inverso design, in which the peptide backbone is reversed and all L-amino acids are replaced with their D-enantiomers, preserves the topochemical presentation of side chains while conferring exceptional resistance to proteolytic degradation. This engineering strategy was specifically applied to target the FOXO4-p53 protein-protein interaction identified as a critical viability-maintaining axis in senescent cells. Produced via solid-phase peptide synthesis, FOXO4-DRI is one of the most widely referenced senolytic peptides.

FOXO4-DRI is a peptide that selectively targets senescent cells by disrupting the FOXO4-p53 interaction within the nucleus. In vitro studies have documented that FOXO4-DRI interferes with the FOXO4-p53 interaction, causing p53 nuclear exclusion and the selective induction of apoptosis in senescent cell populations, and that it binds the disordered transactivation domain 2 of p53 (p53TAD2), to form a transiently folded complex, with p53 phosphorylation increasing affinity for both FOXO4 and FOXO4-DRI [1,2]. In vivo studies in fast-ageing and naturally aged rodent models have examined the compound’s selective clearance of senescent cells, documenting that neutralisation of FOXO4 by FOXO4-DRI restored fitness, fur density and renal function in both fast-ageing mice and naturally aged mice, and counteracted doxorubicin-induced chemotoxicity, alongside reductions in markers of senescence including p16Ink4a [2], making FOXO4-DRI a reference compound in preclinical geroscience research examining FOXO4-p53-axis-directed senolysis and senescent-cell clearance in ageing models.

FOXO4-DRI is manufactured in a cGMP compliant, ISO9001 certified laboratory to a guaranteed purity of 98% or above. Every batch is independently tested using HPLC and MS-UPLC analysis before dispatch. Vials are vacuum sealed and stored in a temperature controlled, monitored cold storage system. Certificates of Analysis are available on request.

Sold strictly for in vitro research purposes only. Not for human consumption. Intended for use by qualified researchers in laboratory settings only.

Editorial Team

Dr. Martina Rossi, PhD

Scientific Contributor and Reviewer

Reviewed and approved 14 June 2026

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