FOXO4-DRI
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FOXO4-DRI

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A designer peptide that interferes with FOXO4–p53 interactions, explored as a senolytic strategy.

Key Research Properties:

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Lyophilized powder form
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$210.00
SKU: foxo4-dri
Purity: >99% (HPLC Verified)
Form: Lyophilized Powder
Storage: Store at -20°C
CAS Number: 2460055-10-9
For Research Use Only.
All products are sold strictly for laboratory and research purposes. Products are not intended for human use or consumption of any kind.

The statements presented on this website have not been evaluated by the Food and Drug Administration (FDA). The products of this company are not intended to diagnose, treat, cure, or prevent any medical condition or disease.

What is FOXO4-DRI?

FOXO4-DRI (FOXO4 D-Retro-Inverso) is a novel senolytic peptide that selectively induces apoptosis in senescent cells by disrupting the FOXO4-p53 interaction[1]. Developed by Peter de Keizer's lab at Erasmus University, FOXO4-DRI represents a breakthrough approach to eliminating senescent cells, which accumulate with age and drive age-related diseases[2].

Selective Senolytic: FOXO4-DRI is one of the first rationally-designed senolytic peptides. It specifically targets senescent cells by disrupting a protein interaction that keeps them alive, causing them to undergo apoptosis while sparing healthy cells. This selective elimination of "zombie cells" shows promise for reversing age-related tissue dysfunction.
Biochemical Properties
  • Structure: D-Retro-Inverso peptide (D-amino acids in reverse sequence)
  • Target: FOXO4-p53 protein-protein interaction
  • Size: ~30 amino acids
  • Developer: Peter de Keizer lab (Erasmus University)
  • Publication: 2017 Cell paper (landmark senolytic study)
  • Mechanism: Competitive inhibition of FOXO4-p53 binding
Primary Benefits
  • Senescent Cell Clearance: Selectively eliminates senescent cells
  • Tissue Rejuvenation: Restores function in aged tissues (animal models)
  • Hair Regrowth: Restores fur in aged mice (dramatic visual effect)
  • Kidney Function: Improves renal function in aged animals
  • Physical Performance: Enhances exercise capacity in aged mice
  • Chemotherapy Recovery: Accelerates recovery from chemotherapy-induced damage

Key Research Findings

Breakthrough Discoveries

  • Selective Senolysis: Induces apoptosis in senescent cells while sparing healthy cells
  • Aged Mouse Rejuvenation: Restored fur, kidney function, exercise capacity in naturally aged mice
  • Chemotherapy Model: Accelerated recovery from chemotherapy-induced senescence
  • FOXO4-p53 Axis: Identified FOXO4-p53 interaction as key senescent cell survival mechanism
  • Tissue-Specific Effects: Benefits observed in kidney, liver, muscle, skin
  • Safety: No apparent toxicity to healthy cells in preclinical studies
Clinical Potential: FOXO4-DRI represents a novel approach to targeting aging at the cellular level. By selectively eliminating senescent cells, it addresses a fundamental driver of age-related tissue dysfunction. The dramatic effects in animal models have generated significant interest in human applications.

Mechanism of Action

FOXO4-DRI works by disrupting the FOXO4-p53 protein interaction that keeps senescent cells alive, releasing p53 to trigger apoptosis selectively in senescent cells[3].

FOXO4-p53 Interaction Disruption

Senescent Cell Survival Mechanism

Background: In senescent cells, FOXO4 binds to p53 and sequesters it away from the nucleus, preventing p53-mediated apoptosis. This keeps senescent cells alive despite DNA damage.

  • FOXO4 Binding: FOXO4-DRI competitively binds to p53, displacing endogenous FOXO4
  • p53 Liberation: Free p53 translocates to nucleus and activates pro-apoptotic genes
  • Selective Apoptosis: Senescent cells (high p53, high FOXO4) undergo apoptosis
  • Healthy Cell Sparing: Normal cells (low FOXO4-p53 interaction) are unaffected
  • Specificity: Selectivity based on elevated FOXO4-p53 in senescent cells

Senescent Cell Apoptosis

Programmed Cell Death Induction

  • p53 Activation: Liberated p53 activates transcription of pro-apoptotic genes (BAX, PUMA, NOXA)
  • Mitochondrial Pathway: BAX/BAK activation; mitochondrial outer membrane permeabilization
  • Caspase Cascade: Cytochrome c release; caspase-9 and caspase-3 activation
  • Cell Death: Apoptotic cell death and clearance by immune system
  • SASP Elimination: Removes source of inflammatory SASP factors

Tissue Rejuvenation

Functional Restoration

  • Inflammation Reduction: Eliminates SASP-secreting cells; reduces chronic inflammation
  • Stem Cell Activation: Removes senescence-induced stem cell dysfunction
  • Tissue Remodeling: Allows healthy tissue regeneration
  • Functional Improvement: Restores organ/tissue function (kidney, liver, muscle)
Mechanism Summary: FOXO4-DRI's mechanism is elegantly simple - it disrupts a specific protein interaction that keeps senescent cells alive, allowing p53 to trigger their elimination. This selectivity makes it a promising senolytic with minimal effects on healthy cells.

Research & Evidence

FOXO4-DRI's landmark 2017 Cell publication demonstrated dramatic rejuvenation effects in aged mice, establishing it as a leading senolytic candidate[4].

Aged Mouse Studies

Natural Aging Model

Key Findings: FOXO4-DRI treatment of naturally aged mice produced dramatic rejuvenation effects.

  • Fur Regrowth: Restored dense fur in aged mice (visible rejuvenation)
  • Kidney Function: Improved renal function markers; reduced fibrosis
  • Exercise Capacity: Increased running distance and endurance
  • Senescent Cell Clearance: Reduced senescent cell markers (p16, SA-β-gal)
  • Safety: No apparent toxicity or adverse effects on healthy tissues

Chemotherapy-Induced Senescence

Accelerated Aging Model

  • Model: Chemotherapy (doxorubicin) induces rapid senescence in mice
  • FOXO4-DRI Treatment: Accelerated recovery from chemotherapy-induced damage
  • Senescent Cell Elimination: Cleared chemotherapy-induced senescent cells
  • Functional Recovery: Improved physical function and tissue health
  • Clinical Relevance: Potential to mitigate chemotherapy side effects

Mechanism Validation

In Vitro & Molecular Studies

  • Selective Killing: Induces apoptosis in senescent cells in vitro; spares proliferating cells
  • FOXO4-p53 Disruption: Confirmed disruption of FOXO4-p53 interaction[8]
  • p53 Transactivation Domain: Recent 2025 Nature Communications study identified disordered p53 TAD as target[8]
  • p53 Activation: Demonstrated p53 nuclear translocation and target gene activation
  • Apoptosis Markers: Confirmed caspase activation and apoptotic cell death

Pulmonary Fibrosis Applications (2022-2023)

Bleomycin-Induced Pulmonary Fibrosis Models

Research Findings: Multiple studies (2022-2023) have demonstrated FOXO4-DRI's efficacy in pulmonary fibrosis models[4][6]:

  • Senescent Cell Clearance: Reduced senescent myofibroblasts in fibrotic lung tissue
  • ECM Reduction: Decreased extracellular matrix production and deposition
  • Fibrosis Amelioration: Improved lung function and reduced fibrotic markers
  • Mechanism: Targets ECM-receptor interaction pathway; reduces TGF-β-induced myofibroblast senescence
  • Comparison: Effects comparable or superior to standard antifibrotic medication (Pirfenidone)

Clinical Potential: Pulmonary fibrosis is a progressive, fatal condition with limited treatment options. FOXO4-DRI's ability to clear senescent fibroblasts suggests potential therapeutic application, though human trials are needed.

Reproductive Health Applications (2020-2024)

Age-Related Reproductive Dysfunction

Research Findings: Studies demonstrate FOXO4-DRI's effects on reproductive aging[2][7]:

  • Testosterone Restoration (2020): Alleviated age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice[2]
  • Spermatogenesis Improvement (2024): Improved spermatogenesis in aged mice through reducing SASP secretion from Leydig cells[7]
  • Mechanism: Eliminates senescent Leydig cells; reduces senescence-associated secretory phenotype (SASP)
  • Outcomes: Increased sperm quality, improved testicular function, restored hormonal balance

Significance: Age-related decline in male reproductive function is a common concern. FOXO4-DRI's ability to restore testicular function suggests potential applications in reproductive medicine, though clinical validation is needed.

Cartilage & Chondrocyte Applications (2021)

Osteoarthritis & Cartilage Degeneration

Research Finding: FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes[3]:

  • Senescent Chondrocyte Clearance: Selectively eliminated senescent chondrocytes in culture
  • Cartilage Health: Reduced senescent cell burden in expanded chondrocyte populations
  • Clinical Relevance: Senescent chondrocytes contribute to osteoarthritis progression
  • Potential Application: May improve outcomes in cartilage repair and osteoarthritis treatment

Keloid & Scarring Applications (2025)

Keloid Senescent Fibroblast Targeting

Recent Research (2025): FOXO4-DRI induces keloid senescent fibroblast apoptosis[10]:

  • Keloid Fibroblasts: Promotes apoptosis of senescent fibroblasts in keloid tissue
  • Mechanism: Promotes nuclear exclusion of upregulated p53-serine 15 phosphorylation
  • Clinical Potential: Keloids are difficult-to-treat fibrotic scars; senolytic approach may offer new treatment strategy

Cancer Applications (2025)

Senescent Cancer Cell Targeting

Recent Research (2025): Peptide inhibitors targeting FOXO4-p53 interactions induce senescent cancer cell-specific apoptosis[9]:

  • Selective Targeting: Induces apoptosis specifically in senescent cancer cells
  • Mechanism: Based on p53 transactivation domain sequence; disrupts FOXO4-p53 binding
  • Research Status: Early-stage investigation; requires further validation
Research Status: FOXO4-DRI has strong preclinical data across multiple disease models (aging, pulmonary fibrosis, reproductive health, cartilage, keloids). Human clinical trials have not been publicly reported. The peptide has generated significant interest in the longevity and biohacking communities, but human safety and efficacy remain to be established. Recent 2025 studies continue to validate and expand potential applications.

Dosing & Administration

Research Use Only: FOXO4-DRI is for research purposes. No clinical trials or FDA approval.

Research Dosing (Extrapolated from Animal Studies)

Subcutaneous Administration

Animal Study Protocol: 5 mg/kg IP, every other day for 3 doses (days 1, 3, 5)

  • Human Equivalent Dose: ~0.8 mg/kg (for 70 kg person: ~56 mg per dose)
  • Community Protocols: Vary widely; typically 10-50 mg per dose
  • Frequency: Every other day for 3 doses (1 week cycle)
  • Cycles: Single cycle; repeat after 3-6 months if desired
  • Route: Subcutaneous injection (animal studies used IP)
  • Timing: No specific timing requirements
Caution: Human dosing is highly speculative. Animal study doses may not translate directly to humans. Community protocols lack clinical validation and safety data.

Reconstitution & Storage

  • Lyophilized Powder: Store at -20°C
  • Reconstitution: Bacteriostatic water for injection
  • Reconstituted Storage: Refrigerate at 2-8°C; use within 7 days
  • Handling: Gently swirl; avoid vigorous shaking

Safety & Side Effects

FOXO4-DRI showed no apparent toxicity in animal studies, but human safety data is lacking[5].

Preclinical Safety

Animal Studies: No apparent toxicity or adverse effects in mice.

  • No Toxicity: No adverse effects on healthy tissues in treated mice
  • Selective Action: Targets senescent cells; spares healthy proliferating cells
  • Organ Function: No adverse effects on liver, kidney, or other organ function
  • Behavioral: No behavioral changes or distress in treated animals
Human Safety Unknown: No published human clinical trials. Community reports vary. Potential concerns include: (1) off-target effects on healthy cells, (2) immune response to senescent cell clearance, (3) unknown long-term effects. Use with extreme caution.
Theoretical Concerns: Senescent cells may have beneficial roles (wound healing, tumor suppression). Excessive senolysis could theoretically impair these functions. However, animal studies showed only benefits, not harm.

Frequently Asked Questions

Senescent cells are "zombie cells" that stop dividing but don't die. They accumulate with age and secrete inflammatory factors (SASP) that damage surrounding tissues. Eliminating senescent cells (senolysis) has shown dramatic rejuvenation effects in animal models, reversing age-related tissue dysfunction.

FOXO4-DRI is a rationally-designed peptide targeting a specific protein interaction (FOXO4-p53) in senescent cells. Other senolytics (dasatinib+quercetin, fisetin) are small molecules with broader mechanisms. FOXO4-DRI's specificity may offer advantages, but comparative human data is lacking.

The most visually striking effect was fur regrowth in aged mice - bald, aged mice regrew thick, youthful fur after FOXO4-DRI treatment. Other significant effects: improved kidney function, increased exercise capacity, and accelerated recovery from chemotherapy. These results generated widespread interest in senolytic therapies.

Unknown. No published human clinical trials exist. Animal studies showed no toxicity, but human safety cannot be assumed. Community use is experimental and carries unknown risks. Clinical trials are needed to establish human safety and efficacy.

No. FOXO4-DRI has not undergone clinical trials and is not FDA-approved. It remains in preclinical research. Available for research purposes only. Human use is experimental and not recommended without proper clinical oversight.

Clinical Trials & Development Status

FOXO4-DRI has strong preclinical data but no publicly reported human clinical trials as of current knowledge[6].

Development Status: FOXO4-DRI remains in preclinical research. Despite dramatic animal study results and significant community interest, no human clinical trials have been publicly reported. Clinical development status is unclear.

Preclinical Foundation

Animal Model Studies

Landmark 2017 Cell Publication: Established FOXO4-DRI as leading senolytic candidate.

  • Natural Aging: Reversed multiple age-related dysfunctions in naturally aged mice
  • Chemotherapy Model: Accelerated recovery from chemotherapy-induced senescence
  • Mechanism Validation: Confirmed FOXO4-p53 disruption and selective senescent cell apoptosis
  • Safety: No apparent toxicity in animal models
  • Reproducibility: Effects replicated across multiple tissues and aging models

Path to Clinical Development

Challenges & Opportunities

  • Peptide Delivery: Peptides face bioavailability challenges; may require optimization
  • Dosing Translation: Animal-to-human dose translation requires careful pharmacokinetic studies
  • Indication Selection: Multiple potential indications (aging, chemotherapy recovery, age-related diseases)
  • Regulatory Path: Novel mechanism; regulatory pathway unclear
  • Commercial Development: Requires significant investment for clinical trials

Community Interest

Longevity & Biohacking Communities

FOXO4-DRI has generated significant interest in longevity-focused communities due to dramatic animal study results. However, human use remains experimental and carries unknown risks without clinical trial data.

Find More Research: Search PubMed: FOXO4-DRI Research
Research Summary: FOXO4-DRI has compelling preclinical data demonstrating selective senolysis and tissue rejuvenation. However, the absence of human clinical trials means safety and efficacy in humans remain unknown. Clinical development is needed to validate this promising senolytic approach.

References & Scientific Citations

Research Integrity:

All references are verified publications from peer-reviewed journals with direct links to sources. FOXO4-DRI research spans from the original 2017 Cell publication through 2025, demonstrating ongoing scientific interest and validation.

Primary Research Citations

  1. Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017;169(1):132-147.e16. [Cell] - PMID: 28340339 - Landmark original study - Established FOXO4-DRI as senolytic peptide
  2. Zhang C, Xie Y, Chen H, Lv L, Yao J, et al. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY). 2020;12(13):12729-12739. [PMC7053614] - PubMed - Cited by 98 - Reproductive aging application
  3. Huang Y, He Y, Makarcyzk MJ, Lin H. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Frontiers in Bioengineering and Biotechnology. 2021;9:677576. [Frontiers] - DOI: 10.3389/fbioe.2021.677576 - Cited by 50 - Cartilage/senescent chondrocyte study
  4. Han X, Yuan T, Zhang J, Shi Y, Li D, et al. FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway. Journal of Cellular and Molecular Medicine. 2022;26(18):4867-4880. [Wiley] - DOI: 10.1111/jcmm.17333 - Cited by 30 - Pulmonary fibrosis application
  5. Zhang R, Gao K, Sadremomtaz A, Ruiz-Moreno AJ. Identification of hotspots in synthetic peptide inhibitors of the FOXO4: p53 interaction. 2022. [Academia.edu PDF] - Cited by 1 - Structural/mechanistic study
  6. Liu Y, Hou Q, Wang R, Liu Y, Cheng Z. FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice. Naunyn-Schmiedeberg's Archives of Pharmacology. 2023;396(8):1801-1813. [Springer] - DOI: 10.1007/s00210-023-02452-2 - Cited by 10 - Pulmonary fibrosis mechanism study
  7. Li Y, Zhang C, Cheng H, Lv LY, Zhu X, Ma M, et al. FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells. Experimental Gerontology. 2024;188:112375. [ScienceDirect] - DOI: 10.1016/j.exger.2024.112375 - Cited by 8 - Male reproductive health
  8. Bourgeois B, Spreitzer E, Platero-Rochart D, et al. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nature Communications. 2025;16:60844. [Nature] - DOI: 10.1038/s41467-025-60844-9 - Cited by 2 - Recent 2025 mechanistic study
  9. Kang D, Lim Y, Ahn D, Lee J, et al. Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis. Journal of Medicinal Chemistry. 2025. [ACS Publications] - Cited by 1 - 2025 cancer application study
  10. Kong YX, Li ZS, Liu YB, Pan B, Fu X, Xiao R, et al. FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation. Nature Communications Biology. 2025;8:7738. [Nature] - DOI: 10.1038/s42003-025-07738-0 - Cited by 2 - 2025 keloid/scarring application
  11. Ross MJ, Baar MP. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Kidney International. 2017;92(5):1055-1057. [Kidney International] - Commentary on original Cell study
  12. Allison SJ. Ageing: targeting senescence-associated tissue damage. Nature Reviews Nephrology. 2017;13(8):449. [Nature Reviews] - Cited by 6 - Review commentary

Disclaimer:

ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY. The products offered are for in-vitro laboratory research use only. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat, or cure any medical condition, ailment, or disease. FOXO4-DRI is NOT approved for human use. All research cited is from preclinical studies only.

Additional Research: Search PubMed for FOXO4-DRI | Google Scholar for FOXO4-DRI Research

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