# FOXO4-DRI

> A senolytic D-retro-inverso peptide that selectively triggers apoptosis in senescent cells by disrupting the FOXO4–p53 interaction.

- Also known as: Proxofim, FOXO4 D-Retro-Inverso peptide
- Class: Longevity
- FDA approved: No
- Canonical page: https://americanpeptide.com/catalog/foxo4-dri

## Overview

FOXO4-DRI is one of the most cited experimental senolytics — peptides designed to clear senescent ("zombie") cells that accumulate with age. It works by disrupting the interaction between the transcription factor FOXO4 and the tumor-suppressor p53, a partnership that senescent cells rely on to avoid self-destruction. Breaking it pushes p53 out of the nucleus and drives those cells into apoptosis, while sparing normal cells. It is built as a D-retro-inverso peptide — the sequence reversed and made from D-amino acids — to resist breakdown in the body.

FOXO4-DRI came out of a 2017 Cell paper from Peter de Keizer’s group (Baar et al., Erasmus MC) that gave the young field of senolytics one of its most striking results. Senescent cells — damaged cells that stop dividing but refuse to die, secreting inflammatory signals — build up with age and drive tissue decline. The insight was that many of them survive by using the protein FOXO4 to keep p53, the cell’s own suicide switch, sequestered and inactive.

FOXO4-DRI is a decoy that occupies FOXO4’s binding site, freeing p53 to trigger apoptosis specifically in cells that depend on that leash. In aged and progeroid mice, the peptide reportedly restored fitness, fur density, and kidney function. To survive as a drug it is synthesized as a D-retro-inverso peptide — the amino-acid order reversed and every residue a mirror-image D-form — which keeps its shape and binding while making it highly resistant to proteases. It is an early-stage research compound (sometimes labeled Proxofim), not FDA-approved, with essentially no human safety data.

## Mechanism

Disrupts the FOXO4–p53 interaction in senescent cells, causing p53 nuclear exclusion and cell-intrinsic apoptosis (a senolytic effect); the D-retro-inverso design confers protease resistance.

## Chemistry

| Property | Value |
| --- | --- |
| Molecular formula | C228H388N86O64 |
| Molecular weight | 5358.2 Da |
| CAS number | 2460055-10-9 |

## Research areas

Studied in: Senescence / senolytics, Aging biology, Tissue regeneration.

Guides on this site:

- [Longevity & Aging](https://americanpeptide.com/research-areas/longevity-aging): Peptides studied across the aging axis — senescence, NAD+, and resilience.

## Key research

- Senolytic mechanism — disrupts the FOXO4–p53 interaction so p53 is excluded from the nucleus, selectively driving senescent cells into apoptosis (Baar et al., Cell 2017).
- Preclinical rejuvenation — reported restoration of fitness, fur density, and renal function in aged and progeroid mice.
- D-retro-inverso design — reversed sequence built from D-amino acids for protease resistance and a long functional half-life.
- Selectivity — targets cells dependent on the FOXO4–p53 leash while sparing normal cells.
- Early-stage — not FDA-approved; human safety essentially uncharacterized.

## Storage, handling & synthesis

**Synthesis.** FOXO4-DRI is a long D-retro-inverso peptide — the sequence reversed and built entirely from D-amino acids for protease resistance. Every residue is a specialty D-building block over a long chain, making it a demanding specialty solid-phase synthesis where all-D coupling efficiency and deletion-sequence control dominate.

## FAQs

### What is FOXO4-DRI?

FOXO4-DRI is a senolytic peptide that selectively kills senescent cells by disrupting the FOXO4–p53 interaction, freeing p53 to trigger those cells’ apoptosis.

### What does "D-retro-inverso" mean?

The peptide’s sequence is reversed and built from D-amino acids (mirror-image residues), which preserves its binding shape while making it highly resistant to protease breakdown.

### What is a senolytic?

A compound that selectively removes senescent ("zombie") cells — damaged cells that stop dividing but resist death and secrete inflammatory signals associated with aging.

### Is FOXO4-DRI approved?

No — it is an early-stage research compound with essentially no human data, not FDA-approved. This page is a research and educational reference.

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Source: AmericanPeptide.com — https://americanpeptide.com/catalog/foxo4-dri
Data license: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Attribution: AmericanPeptide.com.
Research reference only — computational and educational content, not medical advice.