{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:25:28Z","timestamp":1787030728823,"version":"build-2736575974"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>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 1\u03b2 (IL-1\u03b2) 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\u2013PP1\/PP2 axis is a regulatory mechanism in pyroptosis. Pharmacological targeting of AMPK\u2013PP1\/PP2 provides a potential strategy for pyroptosis-related diseases.<\/jats:p>","DOI":"10.3389\/fonc.2026.1737869","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:28:11Z","timestamp":1787027291000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["AMPK\u2013PP1\/PP2 axis regulates GSDMD-mediated pyroptosis via phosphorylation"],"prefix":"10.3389","volume":"16","author":[{"given":"Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiao","family":"Gao","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal and Thyroid Surgery, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weishan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal and Thyroid Surgery, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamin","family":"Xing","sequence":"additional","affiliation":[{"name":"Marshall B. J. Medical Center, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxue","family":"Li","sequence":"additional","affiliation":[{"name":"Marshall B. J. Medical Center, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwei","family":"Guo","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"Department of Oncology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong (Shenzhen), Longgang District People's Hospital of Shenzhen","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zisen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Marshall B. J. Medical Center, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Zheng","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufeng","family":"Chu","sequence":"additional","affiliation":[{"name":"Zhengzhou Key Laboratory of Lipid Metabolism and Precision Diagnosis and Treatment in Oncology, Oncology Department, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences","place":["Zhengzhou, China"]},{"name":"Marshall B. J. Medical Center, The Fifth Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]},{"name":"Immunobiology and Transplant Science Center, Houston Methodist Hospital, Texas Medical Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature18629","article-title":"Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores","volume":"535","author":"Liu","year":"2016","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15514","article-title":"Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death","volume":"526","author":"Shi","year":"2015","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature15541","article-title":"Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling","volume":"526","author":"Kayagaki","year":"2015","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aat2738","article-title":"Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis","volume":"3","author":"Rathkey","year":"2018","journal-title":"Sci Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1186\/s12967-022-03566-6","article-title":"Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level","volume":"20","author":"Zhang","year":"2022","journal-title":"J Transl Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2071-9","article-title":"Gasdermin E suppresses tumour growth by activating anti-tumour immunity","volume":"579","author":"Zhang","year":"2020","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar7607","article-title":"ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation","volume":"362","author":"R\u00fchl","year":"2018","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat Cell Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3311","article-title":"AMPK: A nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"Hardie","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(03)00929-2","article-title":"TSC2 mediates cellular energy response to control cell growth and survival","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-0461-8","article-title":"Energy-stress-mediated AMPK activation inhibits ferroptosis","volume":"22","author":"Lee","year":"2020","journal-title":"Nat Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/s41419-023-06013-6","article-title":"Gasdermin D-mediated pyroptosis is regulated by AMPK-mediated phosphorylation in tumor cells","volume":"14","author":"Chu","year":"2023","journal-title":"Cell Death Dis"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105420","article-title":"The regulation of pyroptosis by post-translational modifications: Molecular mechanisms and therapeutic targets","volume":"109","author":"Zhou","year":"2024","journal-title":"eBioMedicine"},{"key":"B14","doi-asserted-by":"publisher","first-page":"3583","DOI":"10.1038\/s41467-020-17334-x","article-title":"Dissecting the sequence determinants for dephosphorylation by the catalytic subunits of phosphatases PP1 and PP2A","volume":"11","author":"Hoermann","year":"2020","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25147975","article-title":"Histidine phosphorylation: Protein kinases and phosphatases","volume":"25","author":"Ning","year":"2024","journal-title":"IJMS"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1042\/bcj20170726","article-title":"The split protein phosphatase system","volume":"475","author":"Bertolotti","year":"2018","journal-title":"Biochem J"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107386","article-title":"Post-translational control of NLRP3 inflammasome signaling","volume":"300","author":"O\u2019Keefe","year":"2024","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.851169","article-title":"Regulation of inflammatory cell death by phosphorylation","volume":"13","author":"Xu","year":"2022","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1042\/BST20200987","article-title":"PHOrming the inflammasome: Phosphorylation is a critical switch in inflammasome signalling","volume":"49","author":"McKee","year":"2021","journal-title":"Biochem Soc Trans"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1016\/j.jaci.2023.09.020","article-title":"Hypoxia-inducible factor 1\u03b1 activates the NLRP3 inflammasome to regulate epithelial differentiation in chronic rhinosinusitis","volume":"152","author":"Zhong","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000649","article-title":"AKT regulates NLRP3 inflammasome activation by phosphorylating NLRP3 serine 5","volume":"205","author":"Zhao","year":"2020","journal-title":"J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3538","article-title":"NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations","volume":"17","author":"Mortimer","year":"2016","journal-title":"Nat Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02305","article-title":"Regulation of NLRP3 inflammasome by phosphorylation","volume":"9","author":"Song","year":"2018","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01556","article-title":"Tyrosine dephosphorylation of ASC modulates the activation of the NLRP3 and AIM2 inflammasomes","volume":"10","author":"Mambwe","year":"2019","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12964-020-00688-6","article-title":"Inflammasome activation controlled by the interplay between post-translational modifications: Emerging drug target opportunities","volume":"19","author":"Liang","year":"2021","journal-title":"Cell Commun Signal"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01734-6","article-title":"Yersinia infection induces glucose depletion and AMPK-dependent inhibition of pyroptosis in mice","volume":"9","author":"Yang","year":"2024","journal-title":"Nat Microbiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-023-00848-6","article-title":"Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P","volume":"33","author":"Ai","year":"2023","journal-title":"Cell Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01526-w","article-title":"Molecular mechanisms of gasdermin D pore-forming activity","volume":"24","author":"Devant","year":"2023","journal-title":"Nat Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1039\/d2cc03590a","article-title":"Protein phosphatase 1 regulates phosphorylation of gasdermin D and pyroptosis","volume":"58","author":"Li","year":"2022","journal-title":"Chem Commun"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1737869\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:28:11Z","timestamp":1787027291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1737869\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":29,"alternative-id":["10.3389\/fonc.2026.1737869"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1737869","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]},"article-number":"1737869"}}