FOXO4-DRI 10mg

1. What is FOXO4-DRI?

FOXO4-DRI (FOXO4-D-Retro-Inverso) is a synthetic peptide designed to selectively induce apoptosis in senescent cells by disrupting the interaction between FOXO4 and p53. It mimics a critical region of the FOXO4 protein and acts as a senolytic agent—removing dysfunctional, aging cells without affecting healthy ones. FOXO4-DRI is being explored for its potential in regenerative medicine, anti-aging therapies, and age-related disease prevention.

2. “DRI”Retro Inverso Peptides Explained

DRI-Retro Inverso Peptides Explained Retro-inverso peptides are linear peptides whose amino acid sequence is reversed and the a-center chirality of the amino acid subunits is inverted as well. Usually, these types of peptides are designed by including D-amino acids in the reverse sequence to help maintain side chain topology similar to that of the original L-amino acid peptide and make them more resistant to proteolytic degradation. Other reported synonyms for these peptides in the scientific literature are:Retro-Inverso Peptides, All-D-Retro Peptides, Retro-Enantio Peptides, Retro-Inverso Analogs, Retro- Inverso Analogues, Retro-Inverso Derivatives, and Retro-Inverso Isomers. D-amino acids represent conformational mirror images of natural L-amino acids occurring in natural proteins present in biological systems. Peptides that contain D-amino acids have advantages over peptides that just contain L-amino acids. In general, these types of peptides are less susceptible to proteolytic degradation and have a longer effective time when used as pharmaceuticals. Furthermore, the insertion of D-amino acids in selected sequence regions as sequence blocks containing only D-amino acids or in-between L- amino acids allows the design of peptide-based drugs that are bioactive and possess increased bioavailability in addition to being resistant to proteolysis. Furthermore, if properly designed, retro-inverso peptides can have binding characteristics similar to L- peptides. Retro-inverso peptides are useful candidates for the study of protein-protein interactions by designing peptidomimetics that mimic the shape of peptide epitopes, protein-protein, or protein-peptide interfases. Retro-inverso-peptides are attractive

alternatives to L-peptides used as pharmaceuticals. These of peptide have been reported to elicit lower immunogenic responses compared to L-peptides.

FOXO4-DRI releases p53 from physiologic sequestration. The p53 protein then targets senescent cells for apoptosis. The net result is an increase in overall tissue fitness and thus improved function at the tissue and

organ level. Improved tissue function is referred to as reduced biological age.

3.FOXO4-DRI Structure

【pictures linking，https://www.uniprot.org/uniprotkb/P98177/entry】

Sequence:H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-G|u-D-lle-D- Ala-D-GIn-D-Ser-D-lle-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-GIn-D-Asn-D-G|y-D-Trp-D-Ala- D-Asn-D-Arg-D-Arg-D-Ser-D-GIy-D-G|y-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D- Arg-D-GIn-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-GIy-OH

Molecular Formula:C228H388N86O64

Molecular Weight: 5358.05

Synonyms: Forkhead box proteinO4, Proxofim, FOXO4a, AFX, AFX1,MLLT7

4.FOXO4-DRI Research

FOXO4-DRI (Forkhead box O4 D-retro inverso peptide) is a synthetic peptide inhibitor designed to selectively induce apoptosis in senescent cells, while sparing healthy dividing and quiescent cells. Derived from a region of the FOXO4 transcription factor, this designer peptide interrupts the interaction between FOXO4 and p53, triggering programmed cell death in damaged, aging cells.

【1】 Mechanism of Action

Disrupting FOXO4-p53 Interaction: FOXO4-DRI mimics a region of the native FOXO4 protein and competitively binds to p53. This displacement allows p53 to translocate to the nucleus and activate the apoptotic cascade specifically in senescent cells 【https://pubmed.ncbi.nlm.nih.gov/28283060/】.

Senolytic Selectivity: Unlike general chemotherapeutics, FOXO4-DRI targets cells characterized by the senescence-associated secretory phenotype (SASP), minimizing off-target toxicity.

Peptide Stability: As a D-retro-inverso peptide, it is protease-resistant, increasing bioavailability and stability in systemic circulation.

【2】Experimental Evidence

In Aged Mice: Treatment with FOXO4-DRI led to restoration of fur density, improved kidney function, and increased activity in old mice, suggesting systemic rejuvenation (Cell, 2017).

In Progeroid Models: Demonstrated reduction in physical frailty and delayed onset of age-related symptoms.

Ex Vivo Human Cells: Promoted clearance of senescent fibroblasts, restoring proliferation and reducing pro-inflammatory cytokines.

【3】Expert Commentary

Dr. Peter de Keizer, one of the peptide’s developers, stated: “With FOXO4-DRI, we aim to prolong healthy lifespan by addressing cellular damage accumulation—one of the root causes of aging.”

FOXO4-DRI is considered a breakthrough molecule in the emerging field of senotherapeutics.

✅ Why Consider FOXO4-DRI?

🧼 Selective senescent cell clearance without harming healthy cells

♻️ Reverses tissue dysfunction and restores regenerative capacity

🔒 Non-genotoxic, avoiding DNA damage or oncogenesis

🔬 Backed by preclinical success in aging and progeroid models

🧬 Potential adjunct to longevity, anti-aging, and regenerative therapies

5. Future FOXO4-DRI Research

A. Clinical Translation & Safety Profiling

Pharmacokinetics in humans: Trials needed to determine optimal dosing, half-life, and metabolic pathways.

Immunogenicity: Evaluation of immune system reactions to long-term administration.

Delivery Technology: Liposomal and PEGylated versions under exploration for improved targeting.

Long-Term Effects: Understanding how chronic FOXO4-DRI exposure affects stem cell pools, organ regeneration, and cancer resistance.

B. Combination Therapies and Senescence Profiling

Stacking Strategies: Used in conjunction with Dasatinib + Quercetin, Rapamycin, or NAD+ precursors to achieve full-spectrum senolysis.

Senescent Cell Atlas: Mapping which tissues respond best to FOXO4-DRI in different species.

Use in Organ Transplant Prep: Possible pre-conditioning of donor organs by clearing senescent cells to improve graft survival.

Tissue-Specific Optimization: Engineering analogs targeting senescent cells in skin, lung, liver, and neural tissues.

C. Extended Research Models

Cancer Adjunctive Role: Investigating whether FOXO4-DRI can suppress the pro-tumorigenic effects of SASP.

Ophthalmic Use: Senolysis in retinal cells to combat macular degeneration.

Cosmetic Applications: Potential use in anti-aging skincare products targeting skin senescence.

Animal Longevity Trials: Longitudinal data in non-human primates under development.

6. Application Area

Aging & Longevity Therapies

Cellular senescence is a hallmark of aging 【https://pmc.ncbi.nlm.nih.gov/articles/PMC6459707/】

Senolytics like FOXO4-DRI aim to reverse age-related dysfunction

Fibrosis and Organ Health

Liver fibrosis, kidney aging, pulmonary fibrosis

Related study: FOXO4-DRI improves renal fibrosis markers 【https://pubmed.ncbi.nlm.nih.gov/31822439/】

Cosmetic & Dermatological Use

Topical formulations in development for wrinkle reduction and skin regeneration【https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12649】

Neurodegeneration

Role in senescent glial cells and neuroinflammation

Potential synergy with NAD+ and mitochondrial peptides

✅ Summary

FOXO4-DRI is a targeted senolytic peptide that:

Removes dysfunctional senescent cells to restore tissue function

May enhance lifespan and healthspan by clearing cellular debris

Is well-positioned for future clinical translation in aging, oncology, and tissue regeneration

Serves as a foundation for next-gen longevity medicine

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The products offered on this website are furnished for in-vitro studies only. In-vitro studies(Latin: in glass) are performed outside of the body. 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. Bodily introduction of any kind into humans or animals is strictly forbidden by law.