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

Yuan-li Ai1,4, Wei-jia Wang1,4✉, Fan-jian Liu1,4, Wei Fang1,4, Hang-zi Chen 1, Liu-zheng Wu1, Xuehui Hong2✉, Yuekun Zhu3，Ci-xiong Zhang1, Long-yu Liu1, Wen-bin Hong 1, Bo Zhou1, Qi-tao Chen1 and Qiao Wu 1✉© The Author(s) 2023

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.

Cell Research (2023) 0:1–19; https://doi.org/10.1038/s41422-023-00848-6