FOXO4-DRI

FOXO4-DRI is a synthetic 46-residue peptide assembled from D-amino acids with its residue order reversed relative to the parent L-peptide. PubChem indexes it as CID 167312269 under CAS number 2460055-10-9, with the molecular formula C228H388N86O64 and a molecular weight of about 5358 g/mol. The sequence is LTLRKEPASEIAQSILEAYSQNGWANRRSGGKRPPPRRRQRRKKRG. Its first portion corresponds to the region of the FOXO4 forkhead domain that makes contact with p53, and a pair of glycines joins that portion to a reversed basic cell-penetrating segment based on the HIV-1 TAT protein. Material is supplied as a lyophilized (freeze-dried) solid.

D-retro-inverso, abbreviated DRI, describes two changes applied together. Every chiral residue is the D-enantiomer, the mirror image of the L-amino acid found in natural proteins, and the sequence order is reversed. Inverting the stereocentres while reversing the order leaves the side chains in approximately the spatial arrangement of the parent L-peptide, so target binding can be retained, while the backbone is a poor substrate for proteases, which recognise L-configured bonds (PubMed 30582286). Protease resistance is the reason the strategy is used, and it is the distinguishing chemistry of FOXO4-DRI rather than any change to the FOXO4 sequence.

FOXO4-DRI was first described by Baar and colleagues in Cell in 2017, as a tool for testing whether senescent cells can be removed selectively (PubMed 28340339). It is classed as a senolytic: a compound intended to induce apoptosis in senescent cells while sparing dividing ones.

Huang and colleagues applied it to replicatively senescent human chondrocytes expanded in culture (PubMed 33996787). Zhang and colleagues investigated it in aged mice for its effect on senescent Leydig cell burden (PubMed 31959736). Han and colleagues investigated it in a bleomycin mouse lung-injury model for its effect on myofibroblast populations (PubMed 35510614), a paper later corrected (PubMed 39166551).

The evidence base is entirely preclinical. No human study has been published and no human pharmacokinetic or safety data exist. Independent replication remains limited.

In the model set out in the literature, FOXO4 is elevated in senescent cells and holds p53 in nuclear DNA-damage foci, away from the mitochondria. FOXO4-DRI is described as competing for that interaction and releasing p53. Non-senescent cells are not described as depending on this arrangement, the stated basis for the proposed selectivity.

One distinction matters. FOXO4-DRI is not the FOXO4 protein, and not an L-peptide fragment of it: an L-configured peptide of the same residues in native order is a different molecule with different protease stability.

Mechanistic detail is still moving. Bourgeois and colleagues reported that the partner engaged is the disordered p53 transactivation domain, refining the interaction originally proposed (PubMed 40593617). Senescence is scored by marker panels rather than one measurement, and the TAT-derived segment governs cell entry, so uptake and marker choice shape any result.

Sealed lyophilized FOXO4-DRI is held frozen at -20°C, shielded from light, in its original container. Lyophilized peptides are hygroscopic, so a container is brought to ambient temperature before opening.

Repeated freeze-thaw cycles are avoided. Stability for a lot is documented on its Certificate of Analysis.

Reconstitution means returning a lyophilized compound to solution. This entry gives no preparation procedure: solvent and concentration belong to a laboratory protocol, not to a compound description. FOXO4-DRI carries many arginine and lysine residues, giving it a strongly basic, highly polar character, and it is handled as aqueous-soluble material.

Highly cationic sequences adsorb readily to container surfaces, a recognised source of concentration loss. Solubility and water-content figures appear on the lot COA.

Identity and purity of research-grade FOXO4-DRI are established by reverse-phase HPLC and mass spectrometry. Verified purity is documented per lot on the Certificate of Analysis. Chirality is the specification detail that matters most, because mass spectrometry cannot distinguish a D-peptide from its L-enantiomer, so stereochemical assurance rests on the synthesis record.

At 46 residues, deletion sequences are the expected impurity class. Counter-ion content, commonly trifluoroacetate or acetate, shifts peptide mass.

FOXO4-DRI is catalogued alongside these encyclopedia compounds.

• Epitalon.
  Short peptide bioregulator studied in cellular ageing models, on a thinner evidence footing.
• Thymosin Alpha-1.
  28-residue peptide studied in immune-signalling models.
• MOTS-c.
  Mitochondrially encoded peptide investigated in metabolic and cellular-stress models.
• Cartalax.
  Khavinson-series short peptide in the same research grouping.

Baar MP, Brandt RMC, et al. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell.
PubMed 28340339

Rai J (2019). Peptide and protein mimetics by retro and retroinverso analogs. Chem Biol Drug Des.
PubMed 30582286

Zhang C, Xie Y, et al. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY).
PubMed 31959736

Huang Y, He Y, et al. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Front Bioeng Biotechnol.
PubMed 33996787

Bourgeois B, Spreitzer E, et al. (2025). The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nat Commun.
PubMed 40593617

FOXO4-DRI is stocked here in one format: sealed lyophilized vials from two supplier brands, both listed at a 10mg fill. Vials are the only listed format in this catalog. Per-vial strengths are product specifications only. Each lot is batch tested with a published Certificate of Analysis documenting verified purity and identity.

• Browse all FOXO4-DRI research products
• Verified Peptides FOXO4-DRI, 10mg lyophilized vial
• Real Peptides FOXO4-DRI, 10mg lyophilized vial
• Collections: Research Vials. Documentation: COA and Lab Testing.

These products are sold for Research Use Only and are not intended for human consumption.