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

作者：Ai, Yuan-li; Wang, Wei-jia^*; Liu, Fan-jian; Fang, Wei; Chen, Hang-zi; Wu, Liu-zheng; Hong, Xuehui^*; Zhu, Yuekun; Zhang, Ci-xiong; Liu, Long-yu; Hong, Wen-bin; Zhou, Bo; Chen, Qi-tao; Wu, Qiao^*

来源：Cell Research, 2023, 33(12): 904-922.

DOI：10.1038/s41422-023-00848-6

• AUTOPHAGIC CELL-DEATH
• CANCER
• PATHWAY
• GLUCOSE

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 GSDME(T6E) or GSDME(T6A) 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.

• 单位
  厦门大学; 哈尔滨医科大学; 1