# O-GlcNAcylation-regulated classical programmed cell death in diseases: molecular crosstalk and therapeutic opportunities

## TL;DR

This paper reviews how O-GlcNAcylation influences programmed cell death in diseases and explores its potential as a therapeutic target.

## Contribution

The paper provides a comprehensive overview of O-GlcNAc's role in regulating various forms of programmed cell death and its implications for disease treatment.

## Key findings

- O-GlcNAcylation modulates apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis.
- Dysregulation of O-GlcNAc contributes to immune-inflammatory and neurodegenerative diseases.
- Targeting O-GlcNAc could offer therapeutic opportunities for treating diseases.

## Abstract

O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible post translational modification (PTM) involving the attachment of β-N-acetylglucosamine to serine or threonine residues of target proteins. This modification regulates a wide range of cellular functions, including signal transduction, gene expression, protein stability, and cellular metabolism. However, the regulatory patterns of O-GlcNAc in cell death have not been thoroughly summarized or extensively discussed, and detailed mechanistic studies remain limited. This review provides an updated overview of recent advances linking O-GlcNAc with principal types of programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. The occurrence of these forms of PCD plays a critical role in exacerbating immune-inflammatory diseases, neurodegenerative disorders, organ and tissue injury, cardiovascular diseases, and metabolic diseases, whereas in cancer, the induction of PCD can inhibit tumor initiation and progression. Therefore, we focus on the emerging roles of O-GlcNAc in modulating principal types of PCD in these diseases and discuss its potential as a therapeutic target.

O-GlcNAcylation in the regulation of PCD.

Cellular pathway diagram illustrating protein glycosylation processes and related cellular functions. Includes labeled pathways for necroptosis, ferroptosis, and autophagy. Key proteins and cellular components like OGT, OGA, and GlcNAc are highlighted. Receptors and signaling molecules are indicated on the cell membrane, with arrows showing interactions and pathways involved in cellular stress responses, including interactions with bacterial components and oxidative stress.