FOX04-DRI 10mg

FOXO4-DRI — Research Overview

Introduction

FOXO4-DRI, also known as Proxofim, is a synthetic peptide derived from the forkhead box O transcription factor 4 (FOXO4). FOXO proteins (FOXO1, FOXO3, FOXO4, and FOXO6) regulate essential cellular pathways including insulin signaling, cell cycle control, oxidative stress response, and differentiation.FOXO4-DRI is a modified fragment of FOXO4 designed to interfere with the interaction between FOXO4 and the tumor suppressor protein p53. Unlike natural FOXO4, which contains L-amino acids, FOXO4-DRI replaces them with D-amino acids in a retro-inverso sequence, enhancing peptide stability and resistance to degradation. This design allows FOXO4-DRI to selectively influence aging-related processes such as senescence.

Background and Mechanism

– Retro-Inverso Design: By substituting L-amino acids with D-amino acids, FOXO4-DRI maintains functional similarity to FOXO4 while resisting enzymatic breakdown.- p53 Interaction: FOXO4 normally binds p53, preventing its DNA-binding and apoptosis-inducing functions. FOXO4-DRI disrupts this interaction, freeing p53 to resume its tumor suppressor and apoptotic roles.- Senescent Cell Clearance: Senescent cells accumulate with age, contributing to tissue dysfunction through the senescence-associated secretory phenotype (SASP). FOXO4-DRI may restore apoptosis in these cells, reducing their burden and potentially rejuvenating tissue homeostasis.

Chemical Characteristics

Other Titles: Forkhead Box Protein O4-DRI, AFX, FOXO4a, MLLT7

Research Applications

1. Cellular Senescence

– In aged mouse models, FOXO4-DRI exposure was linked to improved physical fitness, renal function, and fur quality.- By targeting FOXO4-p53 interactions, the peptide induced apoptosis in senescent cells, suggesting senolytic potential.

2. Cardiovascular and Proteasome Regulation

– Natural FOXO4 influences proteasome activity but does not directly eliminate damaged cells.- FOXO4-DRI research suggests enhanced clearance of dysfunctional cells, potentially supporting cardiovascular and systemic health.

3. Insulin and Longevity Pathways

– FOXO4 is a key mediator in the insulin/IGF signaling (IIS) pathway, linking external metabolic cues with cellular survival and longevity.- Modulation of IIS by FOXO4-DRI may influence stress resistance and lifespan in research models.

4. Oxidative Stress and Inflammation

– FOXO4 regulates antioxidant enzyme transcription, including MnSOD, catalase, and GPX.- Studies suggest FOXO4-DRI may alter FOXO4 nuclear activity in senescent cells, impacting oxidative stress and inflammatory signaling pathways.

5. Neurological Function

– FOXO proteins have been implicated in neurodegenerative disorders. Dysregulated proteasome activity is observed in these conditions.- Research suggests FOXO4-DRI may help normalize FOXO4 activity in neural tissues, potentially alleviating age-related neurodegeneration.

6. Hypogonadism and Leydig Cell Senescence

– In senescent Leydig cell models, FOXO4-DRI restored p53 activity, leading to apoptosis of dysfunctional cells.- This selective clearance may support testosterone synthesis by reducing senescent cell burden in the testes.

Conclusion

FOXO4-DRI (Proxofim) is a synthetic retro-inverso peptide modeled on FOXO4 that interferes with FOXO4-p53 binding, enabling selective clearance of senescent cells. Research suggests potential benefits in tissue rejuvenation, endocrine regulation, neuroprotection, and stress adaptation. While findings remain experimental, FOXO4-DRI has become a focus of senolytic and anti-aging research.

FOXO4-DRI — References

• Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., van der Pluijm, I., Essers, J., van Cappellen, W. A., van IJcken, W. F., Houtsmuller, A. B., Pothof, J., de Bruin, R. W. F., Madl, T., Hoeijmakers, J. H. J., & de Keizer, P. L. J. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017;169(1):132–147.e16. https://doi.org/10.1016/j.cell.2017.02.031
• de Keizer, P. L. J. The fountain of youth by targeting senescent cells? Trends in Molecular Medicine. 2017;23(1):6–17. https://doi.org/10.1016/j.molmed.2016.11.006
• van Vliet, T., Varela-Eirin, M., de Keizer, P. L. J., Campisi, J., Demaria, M. The senescence-associated secretory phenotype: where do we stand, where are we going? Trends in Cell Biology. 2021;31(8): 664–675. https://doi.org/10.1016/j.tcb.2021.03.007
• Le, A. P., Matzke, M., Kizil, C. Senolytic FOXO4-DRI peptide reduces senescence markers and improves regeneration after traumatic brain injury in zebrafish. Aging (Albany NY). 2020;12(9):8471–8486. https://doi.org/10.18632/aging.103158
• Dookun, E., Walaszczyk, A., Redgrave, R., Palmowski, P., Tual-Chalot, S., Suwana, V., Chapman, J., Jirkovsky, E., Donastorg Sosa, L., Gill, D., Jovanovic, A., Torsney, E., Spyridopoulos, I., Keizer, P. L. J. de, Passos, J. F., Richardson, G. D. Clearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery. Aging Cell. 2020;19(7):e13125. https://doi.org/10.1111/acel.13125
• Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., O’Hara, S. P., LaRusso, N. F., Miller, J. D., Roos, C. M., Verzosa, G. C., LeBrasseur, N. K., Wren, J. D., Farr, J. N., Khosla, S., Stout, M. B., … Kirkland, J. L. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–658. https://doi.org/10.1111/acel.12344
• Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., Hoeijmakers, J. H. J., DePinho, R. A., Bedford, M. T., Campisi, J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental Cell. 2014;31(6):722–733. https://doi.org/10.1016/j.devcel.2014.11.012

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