What Is Foxo4 Dri?

Research Overview

FOXO4-DRI (Proxofim) is a first-in-class senolytic peptide designed to selectively eliminate senescent cells — damaged, non-dividing "zombie" cells that accumulate with age and secrete harmful inflammatory factors known as the Senescence-Associated Secretory Phenotype (SASP). The peptide was developed by Peter L.J. de Keizer and colleagues at the Erasmus University Medical Center Rotterdam and first described in a landmark 2017 publication in Cell.[1]

FOXO4-DRI is derived from the Forkhead domain of the human FOXO4 transcription factor — specifically the region that interacts with p53. Its name reflects two key structural modifications: "D" denotes the use of D-amino acids (mirror images of natural L-amino acids), and "Retro-Inverso" means the amino acid sequence is reversed. Together, these modifications produce a peptide that mimics the 3D surface of the original protein while being highly resistant to enzymatic degradation by proteases. The peptide is further fused to the HIV-TAT protein transduction domain to enable rapid cellular uptake within 2–4 hours.[1][2]

The fundamental insight behind FOXO4-DRI is that senescent cells resist apoptosis by upregulating FOXO4, which binds and sequesters p53 within PML nuclear bodies, preventing p53 from executing its normal pro-apoptotic functions. FOXO4-DRI acts as a competitive decoy, outcompeting endogenous FOXO4 for p53 binding and liberating p53 to translocate to the mitochondria and trigger caspase-dependent apoptosis. Because non-senescent cells express minimal FOXO4 and do not depend on this survival mechanism, they are spared — achieving remarkable selectivity.[1][3]

Preclinical research has demonstrated FOXO4-DRI's therapeutic potential across a broad spectrum of age-related conditions including chemotherapy-induced toxicity, renal function decline, male hypogonadism (testosterone deficiency), vascular aging, pulmonary fibrosis, osteoarthritis, liver fibrosis, and therapy-resistant cancers. The peptide has been shown to restore fur density, physical activity, and kidney function in both fast-aging and naturally aged mice at a standard dose of 5 mg/kg.[1][4][5]

The biotechnology company Cleara Biotech B.V., founded by de Keizer, is advancing optimized 4th-generation variants (CL04183/CL04177) with enhanced binding affinity and improved pharmacokinetic profiles toward clinical development. A structural milestone was reached in 2025 when Bourgeois et al. solved the NMR structure of the FOXO4-DRI/p53 complex, identifying the p53 Transactivation Domain 2 (TAD2) as the specific binding site and demonstrating that p53 phosphorylation at Ser46 and Thr55 enhances binding affinity.[2][3]