Preclinical2017
FOXO4-DRI cleared senescent cells in aged and chemotoxicity-exposed mice, restoring fur density, physical fitness and kidney function without toxicity to non-senescent cells.
Senolytic: Selectively eliminates senescent cells
clinical
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FOXO4-DRI
Senolytic peptide for removing senescent cells and anti-aging
Overview
FOXO4-DRI is a synthetic D-retro-inverso peptide designed to selectively induce apoptosis in senescent cells, a class of dysfunctional cells that accumulate with age and contribute to tissue dysfunction through the senescence-associated secretory phenotype (SASP). The peptide works by disrupting the interaction between FOXO4 and p53 proteins. In senescent cells, FOXO4 sequesters p53 in the nucleus, preventing p53-mediated apoptosis; FOXO4-DRI competes for this binding, releasing p53 to trigger cell death selectively in senescent cells while sparing normal cells. Research in aged mice demonstrated improved fitness, fur density, and renal function following FOXO4-DRI treatment. The D-retro-inverso modification enhances peptide stability and resistance to proteolysis. FOXO4-DRI represents a "senolytic" approach to addressing cellular aging, potentially improving healthspan by clearing accumulated senescent cells. While preclinical results are promising, human clinical trials have not yet been conducted to establish safety and efficacy in humans.
Last reviewed: 2026-08-18
Identity & Aliases
Also known as
FOXO4-DRID-retro-inverso FOXO4 peptideSenolytic peptide FOXO4-DRI
Status: Research compound - Senolytic peptide
Full composition (formula, molecular weight, sequence) in Quick Facts →
Research Areas
Senolytics / cellular senescenceAnti-aging and healthspan researchRenal and tissue regeneration
Available Evidence
Animal
In aged and chemotherapy-treated mice, Baar et al. (2017, Nat Med, PMID 28340347) showed FOXO4-DRI selectively cleared senescent cells and restored physical fitness, fur density, and renal function.
In Vitro
Cell studies demonstrate FOXO4-DRI disrupts the FOXO4-p53 interaction, releasing p53 to induce apoptosis selectively in senescent cells - e.g., senescent human chondrocytes (Front Bioeng Biotechnol 2021, PMID 33996787) and keloid senescent fibroblasts (Commun Biol 2025).
Uncertain
No human clinical data exist; efficacy, dosing, and safety in humans are entirely unknown; the reproducibility of the flagship Nature Medicine findings has been debated, and senolytic approaches remain experimental.
Key Studies & Findings
In Vitro2021
FOXO4-DRI selectively removed senescent cells from in-vitro expanded human chondrocytes, supporting utility in osteoarthritis-related senescence research.
In Vitro2025
FOXO4-DRI induced apoptosis in keloid senescent fibroblasts by promoting nuclear exclusion of p53 (serine-15 phosphorylation), suggesting anti-fibrotic research potential.
Benefits & Effects
Side Effects & Safety
Mild side effect
mildReported (anecdotal only) Reversible
Onset: Immediately
Management: Rotate sites
Limitations & Open Questions
Entirely preclinical (mouse and cell data); no human trials registered; long-term effects, pharmacokinetics, and clinical tolerability unknown; some foundational findings have faced reproducibility questions.
Pharmacology
Synthetic D-retro-inverso peptide designed for proteolytic stability; competes with FOXO4 for binding to p53 in senescent cells, allowing p53 nuclear translocation and apoptosis of senescent cells. No human pharmacokinetic data.
Reported Research Dosing
Reported values from research literature and community protocols. Educational reference only — not a dosing recommendation or medical advice.
Research protocols: Highly variable, typically administered in specialized research settings (Research use only)
Route: SC
Half-life: Hours to days (D-amino acids confer stability)
Research Protocols
Mouse Research Protocol (IV)
- Dose
- 5 mg/kg
- Frequency
- Every other day × 3 doses
- Route
- IV
Mouse Research Protocol (IP)
- Dose
- 5 mg/kg
- Frequency
- Every other day × 3 doses
- Route
- IP
Anecdotal Human Translation (SubQ)
- Dose
- ~25 mg per injection
- Frequency
- Every other day × 3 doses (75-100 mg total per cycle)
- Route
- SubQ
Research protocols are for educational purposes only. Always consult qualified medical professionals.
Frequently Asked Questions
Has FOXO4-DRI been tested in humans?
No. Published evidence is limited to cell and mouse studies; there are no completed or registered human clinical trials for FOXO4-DRI.
What does 'DRI' mean in the name?
It denotes the D-retro-inverso configuration - the peptide is synthesized with D-amino acids in reversed order - which resists enzymatic degradation and improves stability.
Research Citations
3
FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation.
Kong YX, Li ZS, Liu YB, Pan B, Fu X, Xiao R, Yan L (2025)
4
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.
Zhang C, Xie Y, Chen H, Lv L, Yao J, Zhang M, Xia K, Feng X, Li Y, Liang X, Sun X, Deng C, Liu G (2020)
5
FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.
Li Y, Zhang C, Cheng H, Lv L, Zhu X, Ma M, Xu Z, He J, Xie Y, Yang X, Liang X, Deng C, Liu G (2024)
+ 11 more citations
Related Resources
Quick Facts
Formula
C228H388N86O64
Molecular Weight
1.5
Sequence
P
Mechanism
Disrupts senescent cell survival pathways, promoting their elimination
Safety Information
Highly experimental research compound. Extremely limited safety data. Use only in controlled research settings.
Citations
163.FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation.
Kong YX, Li ZS, Liu YB, Pan B, Fu X, Xiao R, Yan L (2025)
4.FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.
Zhang C, Xie Y, Chen H, Lv L, Yao J, Zhang M, Xia K, Feng X, Li Y, Liang X, Sun X, Deng C, Liu G (2020)
5.FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.
Li Y, Zhang C, Cheng H, Lv L, Zhu X, Ma M, Xu Z, He J, Xie Y, Yang X, Liang X, Deng C, Liu G (2024)
+ 11 more citations