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.

细胞焦亡是由gasdermin家族成员执行的一种受调节的细胞死亡。然而，gasdermin 介导的焦亡如何负向调节仍不清楚。在这里，我们证明甘露糖（一种己糖）通过激活 AMP 激活的蛋白激酶 (AMPK) 来抑制 GSDME 介导的细胞焦亡。从机制上讲，己糖胺生物合成途径中的甘露糖代谢会增加代谢物N-乙酰氨基葡萄糖-6-磷酸 (GlcNAc-6P) 的水平，该代谢物与 AMPK 结合以促进 LKB1 磷酸化 AMPK。激活的 AMPK 随后在 Thr6 位点磷酸化 GSDME，从而阻断 caspase-3 诱导的 GSDME 裂解，从而抑制细胞焦亡。 AMPK 介导的 GSDME 磷酸化的调节作用在 AMPK 敲除和 GSDME ^T6E或 GS​​DME ^T6A敲入小鼠中得到进一步证实。在小鼠原发性癌症模型中，给予甘露糖可抑制小肠和肾脏的细胞焦亡，从而减轻顺铂或奥沙利铂诱导的组织毒性，而不损害抗肿瘤作用。甘露糖的保护作用也在一小群接受正常化疗的胃肠道癌症患者中得到验证。我们的研究揭示了甘露糖通过 GlcNAc-6P 介导的 AMPK 激活来拮抗 GSDME 介导的细胞焦亡的新机制，并表明甘露糖补充剂在临床应用中可减轻化疗引起的副作用。