Zhihong Ran, Chuanbao Chen, Junwen Ou, Guozhi Wu, Chao Yang, Xiaoyou Liu
O-GlcNAcylation is a reversible posttranslational modification of proteins that has garnered significant attention in recent years. By regulating the structure and function of proteins, it plays a critical role in various biological processes. Normal O-GlcNAcylation is essential for maintaining internal homeostasis and is involved in controlling fundamental biological events such as gene expression, the cell cycle regulation, metabolism, and signal transduction. Conversely, aberrant O-GlcNAcylation is closely linked to the onset and progression of various diseases-including neurodegenerative diseases, cancers, cardiovascular diseases, and immune-related diseases-where it drives pathological development. Currently, there is a lack of comprehensive reviews systematically addressing the specific mechanisms of O-GlcNAcylation under both physiological and pathological conditions. Therefore, this article aims to summarize its dual role in maintaining organismal homeostasis and promoting disease pathogenesis, providing an integrated evaluation of the biological significance of this modification in health and diseases. Furthermore, it discusses the potential of O-GlcNAcylation as a therapeutic target, explores its clinical applications, and analyzes the current challenges and future directions in drug development, thereby offering theoretical insights and research perspectives for related fields.