FOXO4

FOXO4 is a FOXO-family transcription factor that regulates genes involved in metabolism, cell cycle, apoptosis, and cellular homeostasis^[1]. Mechanistically, FOXO proteins act as context-dependent transcriptional regulators across cellular homeostasis, stem-cell maintenance, apoptosis, metabolism, immunity, and cancer biology^[2]. In senescent cells, FOXO4 functions as a pivot for cell viability by interacting with p53, and FOXO4-DRI perturbs this interaction to drive p53 nuclear exclusion and cell-intrinsic apoptosis^[3]. In disease and aging models, FOXO4-DRI reduced senescent-cell viability, neutralized doxorubicin-induced chemotoxicity, and restored fitness, fur density, and renal function in fast-aging and naturally aged mice^[3]. In aged testicular models, FOXO4 maintained senescent Leydig-cell viability, whereas FOXO4-DRI induced apoptosis and alleviated age-related testosterone secretion insufficiency^[4]. In keloid fibroblasts, FOXO4-DRI promoted apoptosis by nuclear exclusion of upregulated p53-serine 15 phosphorylation^[5]. Compared with related isoforms, mammalian FOXO proteins comprise FOXO1, FOXO3, FOXO4, and FOXO6, and isoform-specific targeting remains important because these proteins show shared and distinct biological functions^[2]. For experimental applications, FOXO4-DRI provides a senolytic tool for interrogating the FOXO4-p53 axis, while structural studies define the p53 transactivation domain as a target of FOXO4 and FOXO4-DRI^[6].