ArticleFrontiers in oncology2026
AMPK-PP1/PP2 axis regulates GSDMD-mediated pyroptosis via phosphorylation.
Article in Frontiers in oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Gasdermin D (GSDMD), the most important executor of pyroptosis, is activated through caspase cleavage to release the N-terminal fragment (GD-NT), which oligomerizes and forms pores in the plasma membrane to induce pyroptosis. We previously reported that AMP-activated protein kinase (AMPK) phosphorylates GD-NT, thereby inhibiting its cytolytic activity. Here, we further investigated the role of phosphorylation in GD-NT-mediated pyroptosis and found that the specific AMPK agonist A-769662 protected tumor cells from GD-NT-mediated pyroptosis and that metformin significantly reduced interleukin 1β (IL-1β) and IL-18 in the peritoneal fluid of lipopolysaccharide (LPS)-induced septic mice. Importantly, we identified PP1/PP2 as the key phosphatases that dephosphorylate GD-NT at Ser46. Treatment of cells with the phosphatase inhibitor okadaic acid (OA) significantly enhanced the phosphorylation of GD-NT and reduced GD-NT-mediated pyroptosis. Therefore, we conclude that the AMPK-PP1/PP2 axis is a regulatory mechanism in pyroptosis. Pharmacological targeting of AMPK-PP1/PP2 provides a potential strategy for pyroptosis-related diseases.
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