Ogt, short for O-GlcNAc transferase, is a key protein in O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification. It catalyzes O-GlcNAcylation by attaching GlcNAc from glycosyl donors to protein Ser/Thr residues, regulating multiple biological processes such as signal transduction, cell cycle, metabolism, and energy homeostasis [2,3,7]. It is involved in pathways like NF-κB signaling [1], and its function is crucial for maintaining cell homeostasis in various cell types [5]. Genetic models, especially KO/CKO mouse models, are valuable tools to study its functions.

Ogt deficiency in mice leads to inflammatory activation of astrocytes both in vivo and in vitro, impairing cognitive function. GlcNAc supplementation to restore O-GlcNAcylation can inhibit astrocyte activation, inflammation, and improve cognitive function. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes its O-GlcNAcylation, while Ogt deficiency promotes Gsk3β binding, activating the NF-κB signaling pathway [1]. In mouse embryonic stem cells, Ogt deficiency blocks cell proliferation due to mitochondrial dysfunction secondary to mTOR hyperactivation. Ogt normally maintains low mTOR activity and mitochondrial fitness by suppressing proteasome activity [4]. In clear cell renal cell carcinoma, Ogt promotes tumor progression by increasing the protein level of HIF-2α through repressing its ubiquitin-proteasome system-mediated degradation [6].

In conclusion, Ogt is essential for many biological processes. Through model-based research, especially KO/CKO mouse models, we've learned that Ogt plays a critical role in processes related to astrocyte activation and cognitive function, cell viability, and cancer progression. These findings contribute to understanding diseases such as neurodegenerative disorders and cancers, providing potential therapeutic targets for treatment.