Specialized Research

FOXO4-DRI

Also known as: FOXO4-D-Retro-Inverso, Proxofim

Molecular Identifiers

Molecular Formula

C228H388N86O64

CAS Number

2460055-10-9

PubChem CID

167312269

Molecular Weight

5358.05 Da

Overview

Senolytic peptide in the D-retro-inverso version of FOXO4, designed to selectively eliminate senescent cells. Uses D-amino acids in reversed sequence for resistance to proteolytic degradation. Acts by disrupting the FOXO4-p53 interaction that keeps senescent cells viable, inducing selective apoptosis of these cells.

Interest around FOXO4-DRI rests on the senolytic hypothesis: by disrupting the FOXO4-p53 interaction that keeps senescent cells viable, it would release p53 to induce selective apoptosis of those cells, reducing senescent burden and the senescence-associated secretory phenotype (SASP). Animal models have reported improvements in fur, renal function, and aging markers, but human evidence is essentially absent.

FOXO4-DRI has no regulatory approval from any agency and is classified as an advanced research peptide. There is no established clinical prescription; when used outside academic settings, it is typically obtained via research suppliers in intermittent protocols with subcutaneous administration. There is no athletic indication.

The peptide was characterized by research groups working on cellular senescence, most notably in the work of Peter de Keizer's group published in 2017, and represents one of the most discussed proofs of concept for peptide senolytics. The D-retro-inverso version confers resistance to protease degradation, extending half-life relative to the native peptide.

Sequence (1 letter): LTLRKEPASEIAQSILEAYSQNGWANRRSGGKRPPPRRRQRRKKRG
Extended notation: H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-Gly-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-Gly-OH

D-retro-inverso peptide (46 aa) — all chiral amino acids are D-enantiomers in reversed sequence relative to native FOXO4, conferring protease resistance. Includes an arginine-rich cell-penetrating domain (HIV-TAT-like) at the C-terminal portion

Half-life

~12-24 hours

Administration Route

Subcutaneous

Category

Specialized Research

Mechanism of Action

  • Disruption of the FOXO4-p53 interaction in senescent cells
  • Induction of selective apoptosis of senescent cells
  • Release of p53 for activation of the mitochondrial apoptotic pathway
  • Reduction of senescent cell burden and senescence-associated secretory phenotype (SASP)

Reported Side Effects

Adverse effects described in the literature. Severity and frequency vary between individuals.

  • Temporary fatigue
  • Gastrointestinal discomfort
  • Mild muscle pain

Product Properties

Purity >98%
Appearance White lyophilized powder
Solubility Soluble in water and bacteriostatic water
Source Solid-phase peptide synthesis (SPPS) with D-amino acids
Storage Lyophilized: -20°C for up to 2 years, 2-8°C for up to 6 months. Reconstituted: 2-8°C for up to 4 weeks. Protect from light and moisture. Avoid repeated freeze-thaw cycles. D-retro-inverso peptides have enhanced stability compared to L-peptides.

Presentations & Preparation

Vials of FOXO4-DRI found in the research market:

5 mg10 mg

Reconstitution

  • Diluent: Bacteriostatic water
  • Volume: 2 ml per vial
  • Inject the diluent slowly against the vial wall
  • Gently swirl until fully dissolved
  • Never shake

Storage

  • Lyophilized: Refrigerated 2-8°C or -20°C for long-term storage
  • Reconstituted: Refrigerated 2-8°C (up to 14 days)
  • Protect from direct light
  • Do not freeze after reconstitution
  • Sensitive peptide — maintain cold chain
Reconstitution Calculator

Scientific Studies

Published studies on FOXO4-DRI.

2021 · Front Bioeng Biotechnol

Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes

Huang Y, He Y, Makarcyzk MJ, Lin H
2017 · Cell

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, et al.

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