Volume 33, No 12, Dec 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 12, December 2023: 904-922   |  Open Access

ORIGINAL ARTICLES

Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P

Yuan-li Ai^1,† , Wei-jia Wang^1,†,* , Fan-jian Liu^1,† , Wei Fang^1,† , Hang-zi Chen¹ , Liu-zheng Wu¹ , Xuehui Hong^2,* , Yuekun Zhu³ , Ci-xiong Zhang¹ , Long-yu Liu¹ , Wen-bin Hong¹ , Bo Zhou¹ , Qi-tao Chen¹ , Qiao Wu^1,*

¹State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
²Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
³Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
^†These authors contributed equally: Yuan-li Ai, Wei-jia Wang, Fan-jian Liu, Wei Fang
Correspondence: Wei-jia Wang(wangwj@xmu.edu.cn)Xuehui Hong(hongxu@xmu.edu.cn)Qiao Wu(qiaow@xmu.edu.cn)

Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.

https://doi.org/10.1038/s41422-023-00848-6

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