FOXO4-DRI | 10mg

Research

Scientific Research on FOXO4‑DRI

FOXO4‑DRI is a synthetic D‑retro‑inverso senolytic peptide designed to mimic the interaction domain of FOXO4 with p53, selectively eliminating senescent cells. Its sequence is H‑FOKDRIASEIAQSILEAYSQNGWANRRSGGrr‑OH (D‑amino acids, retro‑inverso motif LTLRKEPASEIAQSILEAYSQNGWANRRS), followed by a 9‑residue poly‑arginine cell‑penetrating tail, with a molecular mass of approximately 5358 Da. Developed for aging‑related research, FOXO4‑DRI acts as a disruptor of the FOXO4–p53 interaction in senescent cells, where both FOXO4 and p53 are overexpressed.

Mechanism of Action and Inhibition (if applicable)

FOXO4‑DRI enters cells via the poly‑arginine sequence, binds with high affinity to the disordered transactivation domain 2 (TAD2) of p53, and competes with endogenous FOXO4, thereby displacing FOXO4 and promoting nuclear exclusion of phosphorylated p53 (Ser15). This leads to activation of BAX and caspase‑3, triggering selective apoptosis in senescent cells without affecting healthy cells.

No direct inhibitor of FOXO4‑DRI is currently described; its action is senolytic “agonist‑like” via protein‑interaction blockade, with selectivity conferred by the p53‑Ser15 phosphorylation‑dependent binding mode. Co‑immunoprecipitation (CO‑IP) studies confirm disruption of FOXO4–p53 complexes and a reduction in the senescence‑associated secretory phenotype (SASP).

Metabolic and Functional Effects Investigated

In models of bleomycin‑induced pulmonary fibrosis, FOXO4‑DRI eliminates senescent myofibroblasts, reduces inflammatory SASP, downregulates ECM proteins (collagen, fibronectin), inhibits ECM‑receptor interactions, and improves lung function and associated metabolic parameters.

In diabetes‑ and fibrosis‑related models, the peptide increases the proportion of alveolar type‑2 epithelial cells and normal fibroblasts while reducing myofibroblasts, suggesting modulation of TGF‑β and metabolic‑inflammation pathways. In age‑related hypogonadism, FOXO4‑DRI ablates senescent Leydig cells, restoring testosterone and androgenic metabolism in aged mice.

Investigation in Oncological Models

In non‑small‑cell lung cancer (NSCLC; H460/A549 lines), FOXO4‑DRI inhibits proliferation, migration, and colony formation, enhances radiosensitivity through senescence‑associated apoptosis, and induces cell‑cycle arrest.

In keloid‑like aggressive tumor models, the peptide induces apoptosis in pro‑inflammatory, mesenchymal‑type senescent fibroblasts via p53‑Ser15–dependent signaling, reducing recurrence and the senescent‑inflammatory microenvironment. Genomic studies highlight its potential in tumors with therapy‑induced senescence, where it may help prevent chemotherapy‑induced toxicity and relapse.

Pharmacokinetic considerations in research

As a D‑retro‑inverso peptide, FOXO4‑DRI exhibits high proteolytic stability and resistance to enzymatic degradation, coupled with efficient cellular uptake via its poly‑arginine tail. It can be administered systemically (intraperitoneal or intravenous) in murine models, with assumed hepatic/renal clearance similar to other peptides.

A precise half‑life has not been fully quantified in recent literature, but repeated‑dose studies show sustained efficacy without acute hepatorenal toxicity (normal CCK‑8), and extended‑dosing regimens restore function in accelerated‑aging models. The D‑configuration optimizes bioavailability for long‑term preclinical studies.

Other relevant research contexts already explored

• Vascular aging: FOXO4‑DRI suppresses D‑galactose‑ and oxygen‑glucose‑deprivation‑induced endothelial senescence, improves aortic function in aged mice, reduces ROS, and partially restores vascular health.
• Kidney: The peptide restores renal function in aged and progeroid animals, prevents doxorubicin‑induced nephrotoxicity, and alleviates renal fibrosis.
• Reproductive endocrinology: By rejuvenating senescent Leydig cells, FOXO4‑DRI shows promise in age‑related hypogonadism, with potential spillover into idiopathic pulmonary fibrosis (IPF) and immunologically‑driven senolytic strategies. [web

Final considerations

FOXO4‑DRI stands out as a selective senolytic agent for anti‑aging, fibrotic, and selected cancer‑related research, leveraging p53‑dependent selectivity to minimize off‑target effects. Current work focuses on pharmacokinetic optimization and the translation of these findings into clinical trials for age‑related and fibro‑inflammatory diseases.

References

• Wang, Y., et al. (2026). FOXO4‑DRI regulates senescence of endothelial cells via the P53 pathway. Aging, 18(1).
• Ye, X., et al. (2023). Peptide‑mediated therapy in fibrosis: mechanisms, advances, challenges. Biomedicine & Pharmacotherapy, 167.
• Zhang, L., et al. (2023). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS Journal, 290(14).
• Li, H., et al. (2019). The FOXO4 D‑retro‑inverso peptide increases radiosensitivity in non‑small‑cell lung cancer cells. Journal of Southern Medical University, 39(12).

Scientific Reviewer

The content was reviewed by Dr. Ky H. Le, MD. Dr. Ky H. Le is a family physician in Aiea, Hawaii. He received his medical degree from St. George’s University School of Medicine and has practiced for over 20 years. He has expertise in the treatment of obesity, diabetes, hypertension, and high blood pressure, among other conditions. Dr. Ky H. Le accepts Medicare, Aetna, Humana, Blue Cross, and United Healthcare.

Ref.: https://health.usnews.com/doctors/ky-le-371599#expertise