2. Academic Validation
  3. OGT-Mediated O-GlcNAcylation of ATF2 Protects Against Sepsis-Associated Encephalopathy by Inhibiting Microglial Pyroptosis

OGT-Mediated O-GlcNAcylation of ATF2 Protects Against Sepsis-Associated Encephalopathy by Inhibiting Microglial Pyroptosis

  • Neurosci Bull. 2025 May 24. doi: 10.1007/s12264-025-01418-z.
Huan Yao # 1 2,  Caixia Liang # 1,  Xueting Wang 1 3,  Chengwei Duan 1,  Xiao Song 4,  Yanxing Shang 1,  Mingyang Zhang 1 2,  Yiyun Peng 1 2,  Dongmei Zhang 5 6
Affiliations

Affiliations

  • 1 Medical Research Center, Affiliated Hospital 2 of Nantong University, Nantong, 226001, China.
  • 2 Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, China.
  • 3 Institute of Special Environmental Medicine, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
  • 4 Department of Emergency, Affiliated Hospital 2 of Nantong University, Nantong, 226001, China.
  • 5 Medical Research Center, Affiliated Hospital 2 of Nantong University, Nantong, 226001, China. zdm_ntyy@163.com.
  • 6 Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, China. zdm_ntyy@163.com.
  • # Contributed equally.
PMID: 40411666 DOI: 10.1007/s12264-025-01418-z
Abstract

Microglial Pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy (SAE). OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury. However, its regulatory function in microglial Pyroptosis and involvement in SAE remains unclear. In this study, we demonstrated that OGT deficiency augmented microglial Pyroptosis and exacerbated secondary neuronal injury. Furthermore, OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice. Mechanistically, OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation, thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation. In conclusion, this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.

Keywords

Activation transcription factor 2 (ATF2); Microglia; O-GlcNAc transferase (OGT); Pyroptosis; Sepsis-associated encephalopathy (SAE).

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