Foxo4-DRI

Mechanism (as reported)

Structural and mechanistic studies reported that FOXO4-DRI binds the p53 transactivation domain (p53TAD2) and forms a transiently folded complex, with both FOXO4-derived regions and a cationic cell-permeability peptide contributing to the interaction; p53 phosphorylation was reported to enhance affinity for FOXO4 and FOXO4-DRI. Mechanistic work in endothelial and fibroblast contexts reported that FOXO4-DRI disrupts FOXO4–P53 binding, promotes phosphorylated p53 nuclear exclusion, and is associated with activation of apoptosis-related signaling (including BAX and cleaved caspase-3), thereby inducing apoptosis of senescent cells.

Key findings (each cites a source)

• A study in patients with pulmonary arterial hypertension and multiple animal pulmonary hypertension models reported increased lung senescence/DNA-damage markers (including p16, p21, γ-H2AX, and 53BP1) and observed that senescent vascular endothelial cells were decreased after senolytic interventions including FOXO4-DRI. [PMID 36515093]
• In the pulmonary hypertension study, FOXO4-DRI (and other senolytic interventions) were reported to be associated with pulmonary hemodynamic alterations and pulmonary endothelial cell (P-EC) loss in comparison to relevant controls. [PMID 36515093]
• A cell-based study reported that FOXO4-DRI treatment removed more than half of cells in in vitro expanded human chondrocytes at higher expansion (PDL9) while not significantly affecting minimally expanded control cells (PDL3). [PMID 33996787]
• In the chondrocyte study, FOXO4-DRI treatment was reported to reduce senescence levels in PDL9 chondrocytes and to lower senescence-relevant secretory factors; pellet-culture results were reported not to show enhanced chondrogenic potential after FOXO4-DRI pretreatment. [PMID 33996787]
• A cancer/radiation study reported that inducing senescence-like CAF apoptosis using FOXO4-DRI produced radiosensitizing effects on NSCLC cells in vitro and in vivo. [PMID 34877934]
• In that same radiation/cancer study, FOXO4-DRI was reported to have an effect on alleviating radiation-induced pulmonary fibrosis in vivo by targeting senescence-like fibroblasts. [PMID 34877934]
• A molecular structural study reported solution NMR structural models showing FOXO4-DRI binding to the disordered p53 transactivation domain region (p53TAD2) and forming a transiently folded complex; the study also reported that p53 phosphorylation enhances affinity for FOXO4 and FOXO4-DRI. [PMID 40593617]
• A keloid fibroblast study reported that FOXO4-DRI promoted apoptosis and decreased G0/G1 phase cells in pro-senescence keloid organ culture/fibroblast models, accompanied by p53-serine 15 phosphorylation-linked nuclear exclusion. [PMID 39994346]
• A bleomycin-induced pulmonary fibrosis study reported that FOXO4-DRI decreased senescent cells, downregulated SASP components, and attenuated morphological changes and collagen deposition in a mouse model, while also reporting changes in cell populations (increased AEC2 and fibroblasts; decreased myofibroblasts). [PMID 35510614]
• A related pulmonary fibrosis study reported that FOXO4-DRI disrupted the FOXO4-p53 complex and was associated with p53 nuclear exclusion, with milder pathological changes and less collagen deposition in a FOXO4-DRI therapeutic group compared with a BLM-induced group. [PMID 37074394]
• In the fibroblast/pulmonary fibrosis study, FOXO4-DRI was reported to reset intranuclear p53 distribution and decrease total ECM protein content in the tested models. [PMID 37074394]
• A vascular aging/endothelial mechanism study reported that FOXO4-DRI disrupts FOXO4–P53 interaction and is associated with activation of a p53/BCL-2/caspase-3 pathway to promote selective apoptosis of senescent endothelial cells, including effects on phosphorylated p53 nuclear exclusion and downstream markers such as BAX and cleaved caspase-3. [PMID 41625068]