FOXO4-DRI

Also known as: FOXO4-p53 interfering peptide, Senolytic peptide

Evidence: Preclinical

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Overview

Cell-penetrating D-retro-inverso peptide that blocks the FOXO4-p53 interaction, shown in aged mice to selectively kill senescent cells and restore renal function and fitness.

FOXO4-DRI is a 46-residue all-D retro-inverso peptide, built from a FOXO4 segment plus a cationic cell-penetrating carrier, designed to block the FOXO4 interaction with p53 (Baar 2017). In that paper it killed senescent but not control IMR90 human fibroblasts, and in mice given 5 mg/kg intravenously or intraperitoneally on 3 alternate days it neutralized doxorubicin liver toxicity and restored fitness, fur density and renal markers in fast-aging XpdTTD/TTD and naturally aged animals. Later work extended it to aged mouse Leydig cells, spermatogenesis and keloid fibroblasts. One result cuts the other way: in mice and rats, clearing senescent pulmonary endothelial cells with FOXO4-DRI or ABT263 worsened pulmonary hemodynamics (Born 2023). No human study exists and none is registered.

Benefits

Selective apoptosis of senescent cells (human cells in vitro), restored fitness, fur density and renal function in fast-aging and naturally aged mice, improved testosterone output and spermatogenesis in aged mice. No human data by any route

Dosing reference

Research dose: 5 to 10 mg: vendor and community range, no published human dose. Mouse studies used 5 mg/kg intravenously or intraperitoneally on alternate days
Range: 5000 to 10000 mcg, 1x daily (short cycles)
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 5 mg, 10 mg

No human data by any route. The published mouse regimen was 3 doses of 5 mg/kg, intravenous or intraperitoneal, on days 1, 3 and 5, from a 5 mg/mL solution in PBS (Baar 2017), not daily subcutaneous dosing. The 5 to 10 mg figure sold to researchers is a scaled guess with no safety validation. Senolysis is not uniformly beneficial: clearing senescent pulmonary endothelial cells with this peptide worsened pulmonary hemodynamics in mice and rats (Born 2023).

Mechanism

Senescent cells keep p53 in the nucleus through an interaction with FOXO4, which blocks apoptosis. FOXO4-DRI competes for that interaction, p53 is excluded from the nucleus and cell-intrinsic apoptosis follows, selectively in senescent cells (Baar 2017). Solution NMR has since mapped the binding: FOXO4-DRI, itself disordered, binds the disordered second transactivation domain of p53 and forms a transiently folded complex, with the cationic cell-penetrating segment contributing to the interaction rather than only carrying the peptide across the membrane, and p53 phosphorylation increasing affinity for both FOXO4 and the peptide (Bourgeois 2025). The retro-inverso all-D design was chosen for protease resistance; no measurement of its stability or exposure in an animal has been published.

Evidence

Preclinical: animal or in vitro data only

Killed senescent human IMR90 fibroblasts while sparing control cells, with potency increasing over consecutive rounds of treatment; in mice, 3 doses of 5 mg/kg on alternate days neutralized doxorubicin liver toxicity and restored fitness, fur density and renal markers in fast-aging and naturally aged animals (Baar et al., 2017)
In naturally aged mice, FOXO4-DRI induced apoptosis in senescent Leydig cells, reduced senescence-associated secretion and raised testosterone output (Zhang et al., 2020)
In aged mice it improved sperm quality and spermatogenesis, with reduced senescence-associated secretion from Leydig cells (Li et al., 2024)
In human chondrocytes expanded to population doubling level 9 it removed over half the cells and lowered the senescence level, but did not improve chondrogenic potential (Huang et al., 2021)
Contrary result: in SM22-5-HTT+ mice and monocrotaline rats, senolytic clearance of pulmonary endothelial cells with FOXO4-DRI or ABT263 raised right ventricular systolic pressure and worsened vessel remodeling (Born et al., 2023)
Human-trial status: no human study of FOXO4-DRI has been published and no trial is registered on ClinicalTrials.gov. The mechanism has an active commercial program (Cleara Biotech) and patents, but no clinical candidate has entered trials

References

Side effects

No human safety data exist. In mice the published doses were described as well tolerated, with no weight loss over the dosing window (Baar 2017). The principal published risk is not off-target apoptosis but the senolysis itself: eliminating senescent pulmonary endothelial cells worsened pulmonary hemodynamics and vessel remodeling in two rodent models (Born 2023). FDA lists several research peptides sold through the same channels on its compounding safety-risk page; FOXO4-DRI itself is not named there.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not measured in any species. The all-D retro-inverso backbone was chosen to resist proteolysis, and the paper reports no pharmacokinetic data; dosing on alternate days was an empirical schedule
Bioavailability: Not measured. Published animal dosing was intravenous or intraperitoneal; no subcutaneous or oral study exists. Cell entry in vitro is carried by the cationic C-terminal segment, which also contributes to p53 binding
Molecular weight: 5358.2 Da
Sequence: ltlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg (46 residues, all D-configuration, retro-inverso; lower case denotes D-amino acids. The C-terminal krppprrrqrrkkrg segment is the cell-penetrating carrier)