Description
FOXO4-DRI Peptide (Proxofim)
FOXO4-DRI, also known as Proxofim, is a synthetic peptide analog of the endogenous FOXO4 transcription factor. This peptide has drawn significant scientific interest for its potential role in regulating cellular senescence, apoptosis, and tissue regeneration. Researchers have suggested that FOXO4-DRI may interact with the p53 pathway, a key mechanism involved in cell cycle regulation and programmed cell death, making it an important tool for studies on aging, cellular repair, and longevity.
Overview
FOXO4 belongs to the forkhead box O (FOXO) family of transcription factors, which includes FOXO1, FOXO3, FOXO4, and FOXO6. These proteins are known to regulate multiple biological pathways related to insulin signaling, oxidative stress response, metabolism, and cell differentiation.
FOXO4-DRI (D-Retro-Inverso) is a synthetic mirror-image version of a segment of the native FOXO4 protein. In this peptide, the L-amino acids are replaced by D-amino acids, creating a reversed chirality that enhances stability and resistance to enzymatic degradation. This modification allows FOXO4-DRI to maintain functionality while potentially offering improved bioavailability and longevity in experimental conditions.
The FOXO4-DRI peptide specifically targets the interaction between FOXO4 and p53, which is crucial for regulating cellular senescence. Under normal conditions, FOXO4 binds to p53, preventing it from initiating apoptosis in senescent cells. FOXO4-DRI appears to disrupt this binding, allowing p53 to resume its natural role in triggering programmed cell death, thereby selectively eliminating senescent cells — a process referred to as senolysis.
Mechanism of Action
FOXO4-DRI’s proposed mechanism centers on the p53-FOXO4 interaction:
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In senescent cells, FOXO4 binds p53, preventing apoptosis and allowing these dysfunctional cells to persist.
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FOXO4-DRI appears to inhibit this binding, freeing p53 to initiate the natural cell death process.
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This selective removal of senescent cells may promote tissue rejuvenation, reduce inflammation, and restore homeostasis in aging tissues.
Through this mechanism, FOXO4-DRI has been hypothesized to reduce cellular aging markers and improve overall tissue function in various experimental models.
Chemical Composition
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Molecular Formula: C₂₂₈H₃₈₈N₈₆O₆₄
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Molecular Weight: 5358.05 g/mol
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Synonyms: Proxofim, Forkhead Box Protein O4, FOXO4a, AFX, MLLT7
Research and Applications
1. FOXO4-DRI and Cellular Senescence
Studies suggest that FOXO4-DRI may selectively induce apoptosis in senescent cells by restoring p53’s apoptotic function. In 2017 murine studies, aged mice treated with FOXO4-DRI showed improved physical activity, renal function, and fur density, indicating potential rejuvenating effects linked to a reduction in senescent cell burden. These findings suggest a possible role for FOXO4-DRI in cellular repair and age-related tissue decline research.
2. FOXO4-DRI and Cardiovascular Health
Proteasome activity, essential for removing damaged proteins, tends to decline with age. FOXO4-DRI has been proposed to enhance proteasome-mediated clearance of dysfunctional cells, potentially supporting heart and vascular tissue integrity during aging.
3. FOXO4-DRI and Insulin Signaling
FOXO4 is involved in the insulin/IGF signaling (IIS) pathway, which affects cellular growth, metabolism, and longevity. By modulating this pathway, FOXO4-DRI may influence glucose regulation and stress resistance, making it valuable for longevity and metabolic studies.
4. FOXO4-DRI and Oxidative Stress
Research indicates that FOXO4 plays a key role in cellular defense against oxidative stress by activating antioxidant enzymes such as catalase, MnSOD, and GPX. FOXO4-DRI’s interference with FOXO4 translocation may provide insights into redox balance, inflammatory signaling, and aging-related oxidative damage.
5. FOXO4-DRI and Neurological Function
Experimental data suggest that altered FOXO protein levels are linked to neurodegenerative conditions. FOXO4-DRI is being explored for its potential to restore proteasome activity and reduce senescent cell accumulation in neuronal tissues, offering new directions in neurobiology research.
6. FOXO4-DRI and Hypogonadism
In vitro studies using senescent Leydig cells suggest that FOXO4-DRI may target senescent testicular cells, allowing p53-mediated apoptosis to occur. This mechanism may provide valuable insights into age-related testosterone decline and endocrine aging.
Research Summary
FOXO4-DRI Peptide has shown potential in research related to:
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Senolytic activity and selective cell apoptosis
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Tissue rejuvenation and longevity studies
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Oxidative stress and cellular protection
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Insulin signaling and metabolic regulation
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Neurodegenerative and cardiovascular conditions
References
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Babu MM et al., Curr Opin Struct Biol. 2004;14(3):283–291. PubMed
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Sun Y et al., Front Cell Dev Biol. 2021;9:659731. PMC
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Huang Y et al., Front Bioeng Biotechnol. 2021;9:677576. PMC
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Zhang C et al., Aging (Albany NY). 2020;12(2):1272–1284. PMC
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Krimpenfort P, Berns A. Cell. 2017;169(1):3–5. PubMed
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Baar MP et al., Cell. 2017;169(1):132–147.e16. DOI
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Bulteau AL et al., Arch Biochem Biophys. 2002;397(2):298–304. DOI
Important Notice
FOXO4-DRI Peptide (Proxofim) is provided for research and laboratory purposes only. It is not intended for human consumption, medical, or diagnostic use. Researchers should handle all peptides following institutional safety protocols and applicable regulation
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