FOXO1 adenovirus

FOXO1 (Forkhead box O1), historically also known as FOXO1A or FKHR, is a member of the FOXO subfamily of forkhead/winged helix transcription factors that integrates nutrient, growth factor, and stress signals to regulate gene expression. The human FOXO1 gene is located on chromosome 13q14 and encodes a protein with a conserved forkhead DNA-binding domain, nuclear localization and nuclear export signals, and a transcriptional activation region that interacts with coactivators and corepressors. FOXO1 regulates diverse programs involved in cell cycle arrest (e.g., CDKN1B/p27, GADD45), apoptosis (e.g., BCL2L11/BIM, FASL), oxidative stress resistance (e.g., SOD2, catalase), and metabolic control (e.g., PCK1/PEPCK, G6PC, PDK4). In the liver, it is a key effector of fasting-induced gluconeogenesis and lipid metabolism; in adipose tissue, it influences adipogenesis and insulin sensitivity; in endothelial cells, FOXO1 is crucial for vascular development, quiescence, and barrier integrity; and in immune cells and stem cells, it is involved in regulating cell homing, lifespan, and quiescence. Dysregulation of FOXO1 is associated with metabolic diseases, cardiovascular diseases, and cancer. Importantly, chromosomal translocations in alveolar rhabdomyosarcoma produce PAX3–FOXO1 or PAX7–FOXO1 fusion proteins, which have different transcriptional properties than wild-type FOXO1 and serve as oncogenic drivers and biomarkers of aggressive disease.

The FOXO1 adenovirus vector, based on human adenovirus type 5 (Ad5 dE1/E3) with the E1/E3 genes deleted and using the cytomegalovirus (CMV) immediate early promoter to drive human FOXO1A expression, provides a versatile, replication-deficient vector for efficient transient delivery of FOXO1 in a variety of mammalian cell types. In metabolic research, FOXO1 adenoviruses are commonly used to study gluconeogenesis and oxidative gene programs in liver and muscle cells, to elucidate the mechanisms of insulin/AKT-dependent inhibition of FOXO target genes, and to describe their interactions with nuclear receptors and co-regulators, thereby regulating nutrient sensing. In oncology, forced expression of wild-type FOXO1 can mimic tumor suppressor phenotypes, such as growth arrest or pro-apoptotic signaling, aiding in the study of resistance to PI3K-AKT pathway inhibitors and serving as a control for PAX3-FOXO1 fusion protein activity in rhabdomyosarcoma models. In vascular biology, this vector helps to elucidate the role of FOXO1 in endothelial cell quiescence, angiogenesis inhibition, and barrier function; while in adipose tissue and pancreatic research, it aids in the study of adipocyte differentiation, lipolysis, and β-cell stress responses.