Foxo4 Dri: Research Applications

Research Applications

FOXO4-DRI is utilized in preclinical research to study the effects of clearing senescent cells (senolysis) across 9+ research domains:

1. General Aging & Frailty — FOXO4-DRI restores tissue homeostasis in naturally aged mice (104–130 weeks). Benefits include improved fur density, increased physical activity (running wheel activity), improved responsiveness, and reduced p16-driven bioluminescence (senescence burden). Treatment of Xpd^TTD/TTD fast-aging mice yielded fur insulation restoration (approaching wildtype levels) and increased running from 1.37 km/day to near-wildtype levels.[1]
2. Chemotherapy-Induced Toxicity — In Doxorubicin-treated C57BL/6J mice, FOXO4-DRI (5 mg/kg i.v., 3 doses) neutralized chemotherapy-induced liver toxicity (normalized plasma AST), prevented body weight loss, and reduced IL-6 and FOXO4 foci in liver tissue.[1]
3. Renal Function Decline — In both fast-aging and naturally aged mice, FOXO4-DRI normalizes plasma urea and creatinine levels, restoring kidney filtering capacity and reducing tubular senescence markers. Significant reductions observed 30 days after 3 i.p. injections.[1]
4. Male Hypogonadism / Testosterone Deficiency — In aged male mice (20–24 months), FOXO4-DRI selectively induces apoptosis in senescent Leydig cells, reducing SASP factors (IL-1β, IL-6, TGF-β), improving the testicular microenvironment, and significantly restoring serum testosterone levels (p<0.05).[4]
5. Cardiovascular Aging & Endothelial Dysfunction — FOXO4-DRI reduces reactive oxygen species (ROS) in the aorta, suppresses vascular aging markers (p16, p21), thins the aortic wall, lowers Pulse Wave Velocity (improved elasticity), and improves endothelial-dependent vasodilation in both naturally aged and D-galactose progeroid mice.[5]
6. Pulmonary Fibrosis — FOXO4-DRI ameliorates bleomycin-induced pulmonary fibrosis by targeting senescent myofibroblasts, downregulating extracellular matrix receptor interaction pathways, attenuating collagen deposition, and increasing Type 2 alveolar epithelial cells (AEC2).[8][9]
7. Osteoarthritis & Cartilage Regeneration — In expanded human chondrocytes, FOXO4-DRI (25 µM, 5 days) selectively removed >50% of senescent cells (PDL9), reduced SA-β-gal to <5%, and decreased expression of SASP factors (IL-6, IL-8) in engineered cartilage tissue.[6]
8. Cancer & Metastasis — FOXO4-DRI is being explored against therapy-resistant and metastatic cancers (triple-negative breast cancer, metastatic colon cancer) by targeting "scarred" cancer cells that share features with senescent cells, and for radiosensitizing non-small cell lung cancer.[10][11]
9. Liver Fibrosis — FOXO4-DRI and optimized variants (CL04183) counter the CD44-high dedifferentiation state in hepatocytes driven by senescence, restoring liver function markers in fibrosis models.[10]