FOXO4-Dri (10mg) (Proxofim)

What is FOXO4?

FOXO4 is a cellular transcription factor from the Forkhead box O (FOXO) family, involved in regulating stress responses, apoptosis, and cell cycle control. In research, however, scientists often use synthetic FOXO4-derived peptides, such as FOXO4-DRI, which are designed to mimic a critical domain of the native protein.

These peptides are primarily studied for their ability to disrupt the FOXO4–p53 interaction, a mechanism believed to help clear senescent cells. As such, FOXO4 peptides are gaining attention in areas like cellular senescence, longevity research, and age-related tissue repair.

Evolve Peptides’ FOXO4 is formulated with high purity, solubility, and stability, making it ideal for long-term, repeatable research applications.

FOXO4 Mechanism of Action (Based on Research)

FOXO4-DRI (D-retro-inverso FOXO4 peptide) is a synthetic compound engineered to selectively induce apoptosis (programmed cell death) in senescent cells. Its mechanism centers on disrupting a critical interaction between FOXO4 and the tumor suppressor protein p53, which is a key player in cellular aging and DNA damage responses. 

Below are the main pathways through which FOXO4-DRI is believed to act, based on non-clinical research.

Disruption of the FOXO4–p53 Interaction

In senescent cells, the native FOXO4 protein binds to p53, helping retain it in the nucleus and preventing apoptosis. FOXO4-DRI mimics a domain of FOXO4, competitively binding to p53 and blocking this interaction. This interference destabilizes the complex and frees p53 to perform downstream pro-apoptotic functions [1].

This disruption is critical because it removes the molecular “brake” keeping p53 locked inside the nucleus. Without FOXO4 holding it back, p53 is free to initiate apoptosis. This type of cell death is a desired outcome when targeting dysfunctional, senescent cells.

Nuclear Exclusion of p53 and Induction of Apoptosis

Once released from FOXO4, p53 relocates from the nucleus to the mitochondria. This nuclear exclusion of p53 leads to mitochondrial outer membrane permeabilization and activation of caspase-dependent apoptosis. Importantly, this process appears to be selective for senescent cells, as shown in studies involving irradiated fibroblasts and aged tissues [2].

In other words, this step is the execution phase of FOXO4-DRI’s activity. Nuclear exclusion of p53 is a hallmark of pro-apoptotic signaling. Since FOXO4-DRI selectively targets senescent cells, the resulting apoptosis can occur without damaging healthy, dividing cells.

Modulation of p53 Structural Dynamics

Structural analysis using NMR and molecular dynamics simulations suggests FOXO4-DRI enhances binding affinity to p53’s TAD2 domain by promoting transient α-helical conformations, particularly in phosphorylated states of p53 (Ser46, Thr55). This may contribute to its strong competitive inhibition of native FOXO4 binding [1].

This structural modulation likely increases the binding affinity between FOXO4-DRI and p53, strengthening its ability to compete with native FOXO4. It also may amplify p53’s readiness to engage mitochondrial death pathways once released from the nucleus.

Reduction of the Senescence-Associated Secretory Phenotype (SASP)

By removing senescent cells, FOXO4-DRI has been shown to reduce the levels of pro-inflammatory SASP factors like IL-6 and MMPs. In co-culture models with human chondrocytes (cartilage cells), clearing senescent fibroblasts led to improved extracellular matrix expression and reduced inflammatory signaling [3].

By eliminating these aging cells, FOXO4-DRI reduces the chronic inflammation and extracellular matrix degradation associated with SASP. This could create a more favorable environment for tissue repair and regeneration in preclinical models.

Functional Improvements in Non-Clinical Models

Animal studies indicate FOXO4-DRI may restore tissue function in aged organisms. In mouse models, FOXO4-DRI administration led to improved renal and liver function, enhanced spermatogenesis, and partial reversal of age-related decline. It has also shown potential in reducing fibrosis in keloid tissue by inducing selective fibroblast apoptosis [2][4].

These findings highlight the peptide’s potential utility in studying age-related diseases, fibrosis, and tissue dysfunction. While these effects are limited to non-clinical studies, they provide a strong rationale for continued research.

Research Applications (FOXO4 Benefits)

FOXO4-derived peptides, particularly FOXO4-DRI, are being explored in a range of preclinical research areas. These studies focus on the selective removal of senescent cells and the downstream effects this has on tissue health, inflammation, and organ function.

Below are some of the main research domains where FOXO4-DRI has been studied, with summaries of published findings and their potential implications in laboratory settings.

Senescent Cell Clearance in Human Cell Models

One of the most well-established research uses of FOXO4-DRI is in studying its ability to selectively eliminate senescent cells.

FOXO4-DRI has demonstrated selective senolytic activity in various cell culture systems. In human fibroblasts (IMR90), endothelial cells (HUVECs), and over-expanded mesenchymal cells, FOXO4-DRI induced apoptosis specifically in senescent cells without affecting healthy ones. This activity is thought to result from its disruption of the FOXO4–p53 interaction [1][2].

This research supports the peptide’s use as a tool for investigating mechanisms of cellular aging and senescence without triggering widespread cell death.

Application in Cartilage and Chondrocyte Research

In chondrocyte expansion models, such as those used for cartilage repair, FOXO4-DRI has been used to reduce senescent cell populations.

In one study, late-passage human chondrocytes treated with FOXO4-DRI showed lower expression of senescence markers such as SA-β-gal, p16^INK4a, and SASP-related cytokines, while early-passage cells remained unaffected [3].

These findings suggest that FOXO4-DRI may be a useful research tool for improving the quality of cultured cells used in cartilage regeneration experiments, by helping to “clean up” senescent cells that might otherwise impair functional outcomes.

Investigation of Age-Related Testicular Decline

FOXO4-DRI has also been studied in the context of reproductive aging. In a 2021 study, aged mice treated with FOXO4-DRI showed signs of improved testicular function. Specifically, the compound promoted the clearance of senescent Leydig cells, which are responsible for testosterone production.

Treated mice displayed increased testosterone levels and improved histological markers of testicular health, including more organized seminiferous tubules and enhanced spermatogenic activity [5].

These animal studies provide a model for investigating how senescent cell clearance might affect endocrine system aging and reproductive function in mammalian systems.

Restoration of Tissue Function in Naturally Aged Mice

One foundational study showed that FOXO4-DRI administration in both progeroid and naturally aged mice led to measurable improvements in several physiological parameters.

Treated animals exhibited restored fur density, increased physical activity, improved renal and hepatic function, and a general reduction in senescence markers across various tissues. In these models, FOXO4-DRI acted systemically to reduce the burden of senescent cells, which are thought to drive tissue dysfunction during aging [2].

This area of research supports the use of FOXO4-DRI in exploring how cellular senescence contributes to multi-organ decline and frailty over time.

Use in Fibrosis and Cancer Senescence Studies

Recent studies have extended the potential research applications of FOXO4-DRI to include models of fibrosis and cancer.

In a murine model of idiopathic pulmonary fibrosis (IPF), FOXO4-DRI treatment was associated with reduced levels of senescent myofibroblasts and decreased lung stiffness, suggesting its utility in understanding senescence-driven fibrotic remodeling.

Separately, a 2021 study explored how a modified FOXO4 peptide (ES2) synergized with BRAF inhibition to selectively eliminate senescent melanoma cells, improving survival and reducing tumor burden in mouse models [4][6].

These findings provide a basis for using FOXO4-DRI in models that investigate the role of senescence in tumor progression, drug resistance, and fibrotic disease mechanisms.

FOXO4 Characteristics

• Molecular Formula: C₂₂₈H₃₈₈N₈₆O₆₄
• CAS Number: 2460055-10-9
• Molar Mass: ~5,358.06 Da
• Amino Acid Sequence: 
  • D-(Leu-Thr-Leu-Arg-Lys-Glu-Pro-Ala-Ser-Glu-Ile-Ala-Gln-Ser-Ile-Leu-
  • Glu-Ala-Tyr-Ser-Gln-Asn-Gly-Trp-Ala-Asn-Arg-Arg-Ser-Gly-Gly-Lys-Arg-
  • Pro-Pro-Pro-Arg-Arg-Arg-Gln-Arg-Arg-Lys-Lys-Arg-Gly)
  • Also listed as D-(LTLRKEPASEIAQSILEAYSQNGWANRRSGGKRPPPRRRQRRKKRG)
• Synonyms: FOXO4‑DRI; D‑Retro‑Inverso FOXO4; D‑Retro‑Inverso Forkhead box protein O4; FOXO4 D‑Retro Inverso peptide
• Storage Recommendations:
  • Lyophilized Powder: Store at −4°F (−20°C) in a dry, desiccated environment. Stable for up to 36 months under these conditions.
  • Reconstituted Solution: Store at −4°F (−20°C) for short-term use (up to 6 months)
  • For long-term storage, keep at −112°F (−80°C)
  • Avoid repeated freeze–thaw cycles to preserve peptide integrity.

FOXO4‑DRI vs Dasatinib + Quercetin (D+Q) vs Navitoclax Comparison

FOXO4 Safety and Side Effects in Studies

Most data on FOXO4‑DRI originates from preclinical research, primarily in cell culture and animal models. Note that no formal human clinical trials or regulatory evaluations have been completed.

FOXO4‑DRI shows promising senolytic specificity and tolerability in lab and animal models, with no reported adverse effects at research dosages. However, long-term toxicity, pharmacokinetics, tissue-specific safety, and human tolerability remain entirely uncharacterized.

In cell–based and murine studies, FOXO4‑DRI induced apoptosis specifically in senescent cells, with little to no impact on healthy cells, body weight, or organ function at typical dosing. Studies using multiple administrations have not noted adverse effects or organ toxicity. Animals maintained weight and showed no behavioral or metabolic decline [7][8].

Certificate of Analysis (COA)

At Evolve Peptides, each batch of FOXO4‑DRI undergoes comprehensive third-party laboratory testing. Batch-specific Certificates of Analysis (COAs) are linked to every vial, ensuring full traceability and confidence in purity and identity.

The certificate provides information on:

• Peptide Identity Verification: Confirmed via techniques like Mass Spectrometry or HPLC
• Purity Analysis: Always ≥ 99% as certified by independent labs
• Structural Confirmation: Ensuring correct peptide sequence and integrity
• Batch Number & Production Date: For documentation and reproducibility
• Storage & Handling Conditions: As per best laboratory practices

Each product page features a link to view/download the batch-specific COA PDF. You’re also welcome to have peptides tested by your own third-party labs, and we will replace any vials used during such testing—just submit your COA and order number

Legal Disclaimer

This product is intended strictly for qualified laboratory research use only. It is not approved by the FDA or any other regulatory agency for human consumption, therapeutic use, diagnostic procedures, or veterinary applications.

• Not for human or animal use.
• Not for medical, clinical, or household use.
• Not for resale or inclusion in dietary, cosmetic, or pharmaceutical formulations.
• Not a drug, food, or supplement.

The purchaser assumes full responsibility for the safe handling, proper storage, and lawful use of this compound in accordance with all applicable regulations and guidelines.

By purchasing from Evolve Peptides, you confirm that you are a qualified researcher or licensed laboratory and understand the risks associated with experimental compounds.

This product is not intended to diagnose, treat, cure, or prevent any disease.

Scientific References

1. Bourgeois, B., Spreitzer, E., Platero‑Rochart, D., Paar, M., Zhou, Q., Usluer, S., Keizer, P. L. J., Burgering, B. M. T., Sánchez‑Murcia, P. A., & Madl, T. (2025). The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4‑DRI. Nature Communications, 16(1), Article 60844. https://www.nature.com/articles/s41467-025-60844-9
2. Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., … Van Deursen, J. M. (2016). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132–147. https://www.cell.com/cell/fulltext/S0092-8674(17)30246-5
3. Huang, Y., He, Y., Makarcyzk, M. J., Lin, H., et al. (2021). Senolytic peptide FOXO4‑DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, Article 677576. https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2021.677576/full
4. Kong, Y.-X., Li, Z.-S., Liu, Y.-B., Pan, B., Fu, X., Xiao, R., … Yan, L. (2025). FOXO4‑DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53‑serine 15 phosphorylation. Communications Biology, 8(1), Article 299. https://www.nature.com/articles/s42003-025-07738-0
5. Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021, April 29). Senolytic peptide FOXO4‑DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, Article 677576. https://pubmed.ncbi.nlm.nih.gov/33996787/
6. Le HH, Cinaroglu SS, Manalo EC, Ors A, Gomes MM, Duan Sahbaz B, Bonic K, Origel Marmolejo CA, Quentel A, Plaut JS, Kawashima TE, Ozdemir ES, Malhotra SV, Ahiska Y, Sezerman U, Bayram Akcapinar G, Saldivar JC, Timucin E, Fischer JM. Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells. EBioMedicine. 2021 Nov;73:103646. doi: 10.1016/j.ebiom.2021.103646. Epub 2021 Oct 21. PMID: 34689087; PMCID: PMC8546421. https://pmc.ncbi.nlm.nih.gov/articles/PMC8546421/
7. A FOXO4 Inhibitory Peptide Limits Chemotoxicity in Mice. Cancer Discov 1 June 2017; 7 (6): OF21.https://aacrjournals.org/cancerdiscovery/article/7/6/OF21/5897/A-FOXO4-Inhibitory-Peptide-Limits-Chemotoxicity-in
8. 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. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY). 2020 Jan 20;12(2):1272-1284. doi: 10.18632/aging.102682. Epub 2020 Jan 20. PMID: 31959736; PMCID: PMC7053614. https://pmc.ncbi.nlm.nih.gov/articles/PMC7053614/