FOXO4-DRI Peptide: Structure, Research & Science Guide

By The Peptides Codex Editorial TeamReviewed September 8, 2026

Page data last changed: 2026-10-05. Chemistry registry snapshot: 2026-10-01. Registry refreshes and identity assessments are separate from scientific content review.

Length

n/a

Class

Cell-permeable D-retro-inverso senolytic peptide

Function

Disrupts the FOXO4–p53 interaction in senescent cells, releasing p53 to trigger apoptosis

Context

Investigational preclinical compound; no registered clinical trial and not approved anywhere

The first peptide senolytic: it works by prying p53 away from FOXO4 in senescent cells — and a 2023 Circulation study shows why clearing senescent cells is not automatically safe.

Also known as: FOXO4 D-retro-inverso peptide · FOXO4-DRI TFA · Proxofim

Part of the Foundational & therapeutic peptides cluster

Overview

FOXO4-DRI is a synthetic D-retro-inverso peptide designed to disrupt the interaction between the transcription factor FOXO4 and p53 inside senescent cells, freeing p53 to drive those cells into apoptosis. Mouse studies report restored testosterone output from aged Leydig cells, improved spermatogenesis, reduced pulmonary fibrosis and selective removal of senescent chondrocytes; a 2025 Nature Communications paper mapped its target to p53's disordered transactivation domain. It has no human trials and is not approved anywhere.

Source & context

Biological / chemical source: Synthetic peptide built from D-amino acids in reversed sequence order, modelled on a FOXO4 fragment fused to a cell-penetrating segment

Primary research or clinical context: Investigational preclinical compound; no registered clinical trial and not approved anywhere

What FOXO4-DRI is

FOXO4-DRI is a synthetic peptide built on the retro-inverso principle: the sequence of a natural fragment is reversed and every residue is switched to its D-form, which preserves the side-chain surface a partner protein recognises while making the chain almost immune to proteases. The fragment in question comes from the transcription factor FOXO4, and the peptide is fused to a cell-penetrating segment so it can reach the nucleus. PubChem records the trifluoroacetate salt as compound 167312269 with a mass of about 5.4 kDa. It is sold in the grey market under the trade-style name Proxofim.

Mechanism: releasing p53 in senescent cells

Senescent cells — cells that have permanently stopped dividing but resist death — accumulate with age and secrete inflammatory factors. In them, FOXO4 binds p53 in the nucleus and keeps it from triggering apoptosis (Li et al., Experimental Gerontology 2024). FOXO4-DRI competes for that interaction, displacing p53 so it can act (Hu et al., Frontiers in Bioengineering and Biotechnology 2025). A 2025 structural study identified the target precisely: the disordered transactivation domain of p53 is what FOXO4 — and the senolytic peptide — bind (Bourgeois et al., Nature Communications 2025). Downstream, the peptide activates the p53/BCL-2/caspase-3 pathway and drives selective apoptosis of senescent cells (Hu et al. 2025).

Mouse studies: reproduction and ageing

In aged mice, FOXO4-DRI targeted senescent Leydig cells and alleviated the age-related insufficiency of testosterone secretion (Zhang et al., Aging 2020), and improved spermatogenesis by reducing senescence-associated secretory phenotype output from Leydig cells (Li et al., Experimental Gerontology 2024). In naturally aged and progeroid mice it improved vascular function and delayed vascular ageing by clearing senescent endothelial cells (Hu et al., Frontiers in Bioengineering and Biotechnology 2025).

Mouse and cell studies: fibrosis, cartilage, keloids

FOXO4-DRI ameliorated bleomycin-induced pulmonary fibrosis in mice, in one study by targeting myofibroblasts through the ECM–receptor interaction pathway (Han et al., Journal of Cellular and Molecular Medicine 2022) and in another by reducing extracellular-matrix production in fibroblasts (Liu et al., Naunyn-Schmiedeberg's Archives of Pharmacology 2023). It selectively removed senescent cells from in vitro-expanded human chondrocytes destined for cartilage repair (Huang et al., Frontiers in Bioengineering and Biotechnology 2021) and induced apoptosis of senescent keloid fibroblasts by promoting nuclear exclusion of phosphorylated p53 (Kong et al., Communications Biology 2025).

Reported preclinical findings
Model	Reported effect	Source
Aged mice — Leydig cells	Restored testosterone secretion	Zhang et al., Aging 2020
Aged mice — testis	Improved spermatogenesis, lower SASP output	Li et al., Exp Gerontol 2024
Aged and progeroid mice — aorta	Improved vascular function	Hu et al., Front Bioeng Biotechnol 2025
Mice — bleomycin lung fibrosis	Reduced fibrosis	Han et al. 2022; Liu et al. 2023
Human chondrocytes in vitro	Selective removal of senescent cells	Huang et al. 2021
Mice — hypoxia/monocrotaline pulmonary hypertension	Senescent-cell clearance PROMOTED pulmonary hypertension	Born et al., Circulation 2023

The cautionary result

Clearing senescent cells is not uniformly beneficial. In mouse and rat models of pulmonary hypertension, eliminating senescent cells — by a suicide-gene construct, by the senolytic drug ABT263, and by FOXO4-DRI — promoted the development and progression of pulmonary hypertension rather than preventing it (Born et al., Circulation 2023). The authors had found abundant senescence markers in the lungs of patients with pulmonary arterial hypertension, and the expectation was that removing those cells would help. The opposite occurred. For a peptide sold online as an anti-ageing agent, this is the single most important paper in its literature.

What has not been studied

There is no human trial of FOXO4-DRI: ClinicalTrials.gov lists none, and the PubMed literature is entirely mouse, rat and cell-culture work. Pharmacokinetics in any species beyond what the mouse studies imply, dose–response in humans, effects on non-senescent cells that also rely on the FOXO4–p53 axis, and long-term consequences of repeated senolysis are all uncharacterised. The D-retro-inverso design that gives the peptide protease resistance also means it persists longer than ordinary peptides, which cuts both ways.

Status and what this page is not

FOXO4-DRI is a preclinical research compound, not approved anywhere and not in clinical development. Material sold online as Proxofim or FOXO4-DRI is unregulated, and marketing it for human use is illegal in the US, Canada and the EU. This profile summarises the published science, including the adverse finding; it is not guidance on obtaining or using any product, and it is not medical advice.

Structure & chemistry

Molecular identity & reference confidence

Source-supported reference

Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.

Molecular form: D-retro-inverso peptide — D-amino acids assembled in reverse order to mimic the native L-peptide surface while resisting proteolysis; includes a cell-penetrating segment
Species: Not established by this molecular identity audit
Termini (N / C): Not specified / Not specified

Average reference mass

Reference policy updated: 2026-10-05

PubChem molecular record · 2026-10-01

Molecular formula: C228H388N86O64
Average reference mass: ≈ 5,358
Receptors: No receptor: an intracellular protein–protein interaction inhibitor targeting the FOXO4 binding site on p53's transactivation domain
Backbone: D-retro-inverso peptide — D-amino acids assembled in reverse order to mimic the native L-peptide surface while resisting proteolysis; includes a cell-penetrating segment
Status: Preclinical; no registered clinical trial and not approved anywhere (September 2026)

Identifiers

PubChem CID: 167312269
CAS RN: 2460055-10-9

Chemistry values: curated profile, PubChem · fetched 2026-10-01.

Concentration math

FOXO4-DRI — reconstitution calculator

Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.

Reference form: D-retro-inverso peptide — D-amino acids assembled in reverse order to mimic the native L-peptide surface while resisting proteolysis; includes a cell-penetrating segmentAverage reference mass: 5,358 Da

Peptide in vial (mg)

Diluent added (mL)

Syringe graduation

Solution concentration

5 mg/mL5,000 mcg/mL

Amount to measure (optional)

mcg

Enter an amount to see the volume it corresponds to.

Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.

Open the FOXO4-DRI calculator on its own page →

Change log

Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.

2026-09-08IdentifiersCross-linked to PubChem CID 167312269.
2026-09-08EditorialProfile content reviewed and updated by the editorial team.

FAQ about FOXO4-DRI

What is FOXO4-DRI?+

What Canadian product status is recorded for FOXO4-DRI?+

Canadian product status for FOXO4-DRI has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.

What is the typical length of FOXO4-DRI?+

FOXO4-DRI is not a classic amino-acid chain peptide in the same sense; see the profile for classification details.

What is FOXO4-DRI?+

A synthetic D-retro-inverso peptide that disrupts the FOXO4–p53 interaction in senescent cells, releasing p53 to trigger their apoptosis — a peptide senolytic.

How does FOXO4-DRI work?+

It binds the disordered transactivation domain of p53 where FOXO4 normally binds, displacing FOXO4 and activating the p53/BCL-2/caspase-3 apoptosis pathway in senescent cells.

Has FOXO4-DRI been tested in humans?+

No. All published evidence is in mice, rats and cultured cells; no clinical trial is registered.

Is FOXO4-DRI safe?+

Unknown in humans. In animal models of pulmonary hypertension, clearing senescent cells with FOXO4-DRI promoted the disease rather than preventing it (Circulation 2023).

Is FOXO4-DRI approved?+

No, nowhere.

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References & further reading

Disclaimer: Educational content only. Not medical advice. Not instructions for human use. Research peptides and unapproved products may be restricted or illegal to market for human consumption in your jurisdiction. Consult qualified professionals and applicable law.

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