FOXO6: A unique transcription factor in disease regulation and therapeutic potential

FOXO6, a unique member of the Forkhead box O (FOXO) transcription factor family, has emerged as a pivotal regulator in various physiological and pathological processes, including apoptosis, oxidative stress, autophagy, cell cycle control, and inflammation. Unlike other FOXO proteins, FOXO6 exhibits distinct regulatory mechanisms, particularly its inability to undergo classical nucleocytoplasmic shuttling. These unique properties suggest that FOXO6 may function through alternative pathways, positioning it as a novel research target. This review provides the first comprehensive review of FOXO6's biological functions and its roles in the progression of multiple diseases, such as cancer, metabolic disorders, neurodegenerative conditions, and cardiovascular dysfunction. We highlight FOXO6's interaction with critical signaling pathways, including PI3K/Akt, PPARγ, and TXNIP, and discuss its contributions to tumor progression, glucose and lipid metabolism, oxidative stress, and neuronal degeneration. Moreover, FOXO6's potential as a therapeutic target is explored, with particular emphasis on its ability to modulate drug resistance and its implications for disease treatment. Despite its promising therapeutic potential, the development of FOXO6-targeted therapies remains challenging due to overlapping functions within the FOXO family and the context-dependent nature of FOXO6's regulatory roles. This review underscores the need for further experimental and clinical studies to elucidate the molecular mechanisms underlying FOXO6's functions and to validate its application in disease prevention and treatment. By systematically analyzing current research, this review aims to provide a foundational reference for future studies on FOXO6, paving the way for novel therapeutic strategies targeting this unique transcription factor.