O-GlcNAcylation mediates H2O2-induced apoptosis through regulation of STAT3 and FOXO1

Chen-chun Zhang1,2, Yuan Li1,2, Chang-you Jiang1,2, Qiu-min Le1,2, Xing Liu1,2, Lan Ma1,2, Fei-fei Wang1,2
1 School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai 200032, China
2 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai 200032, China
Correspondence to: Fei-fei Wang:,
DOI: 10.1038/s41401-023-01218-z
Received: 4 May 2023
Accepted: 14 December 2023
Advance online: 8 January 2024


The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H2O2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H2O2-induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H2O2-treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H2O2-induced apoptosis of N2a cells.

Keywords: O-GlcNAcylation; oxidative stress; apoptosis; STAT3; FOXO1

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