Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis
Abstract Gasdermin D (GSDMD)‐induced pyroptosis is associated with inflammatory disease. However, the role of GSDMD in acute pancreatitis (AP) is not yet fully elucidated. This study reveals that GSDMD serves two distinct functions in pancreatic acinar cells and macrophages. In acinar cells, GSDMD i...
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2025-08-01
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| Online Access: | https://doi.org/10.1002/advs.202502412 |
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| author | Chaoxu Liu Ning Liang Chen Wu Zhaoyan Qiu Qian Huang Xiaolong Wei Shurong Zhang Shuanghong Lei Tao Yang Gang Wang Qian Wang |
| author_facet | Chaoxu Liu Ning Liang Chen Wu Zhaoyan Qiu Qian Huang Xiaolong Wei Shurong Zhang Shuanghong Lei Tao Yang Gang Wang Qian Wang |
| author_sort | Chaoxu Liu |
| collection | DOAJ |
| description | Abstract Gasdermin D (GSDMD)‐induced pyroptosis is associated with inflammatory disease. However, the role of GSDMD in acute pancreatitis (AP) is not yet fully elucidated. This study reveals that GSDMD serves two distinct functions in pancreatic acinar cells and macrophages. In acinar cells, GSDMD inhibits the synthesis of pancreatic enzyme by downregulating the expression of Prss1, Pnlip, and Amy1 via the inhibition of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 (RPS6)/eukaryotic translation initiation factor 4E‐binding protein 1 (4EBP1) pathway. Moreover, GSDMD induces pancreatic acinar cells to express mucin 1 (MUC1) by activating the nuclear factor kappa‐B (NF‐κB) pathway, which forms a barrier that prevents digestive enzyme‐mediated digestion. However, GSDMD promotes the secretion of inflammatory cytokines by macrophages during AP. In addition, GSDMD increases the infiltration of macrophages and neutrophils in AP and increases the proportion of Th1 and Th17 lymphocyte subsets in peripheral blood. However, in general, the harmful effect of GSDMD in AP outweighs its beneficial effect, and GSDMD knockout can effectively alleviate AP. These findings indicate that GSDMD may be a potential target for the treatment of AP; however, its dual effects need to be comprehensively considered. |
| format | Article |
| id | doaj-art-7ccbd2435eca44b49c9355a87ba39cea |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
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| spelling | doaj-art-7ccbd2435eca44b49c9355a87ba39cea2025-08-23T14:14:10ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202502412Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute PancreatitisChaoxu Liu0Ning Liang1Chen Wu2Zhaoyan Qiu3Qian Huang4Xiaolong Wei5Shurong Zhang6Shuanghong Lei7Tao Yang8Gang Wang9Qian Wang10Department of Colorectal Surgery The First Affiliated Hospital of Zhejiang University Hangzhou 310006 ChinaDepartment of Gastroenterology 920th Hospital of the Joint Logistics Support Force PLA Yunnan Kunming 650032 ChinaDepartment of General Surgery Huashan Hospital, Fudan University Shanghai 201907 ChinaDepartment of General Surgery the First Medical Centre Chinese PLA General Hospital Beijing 100853 ChinaDepartment of Gynaecology and Obstetrics The 75th Group Army Hospital Dali 671000 ChinaDepartment of Gastroenterology 920th Hospital of the Joint Logistics Support Force PLA Yunnan Kunming 650032 ChinaDepartment of Gastroenterology 920th Hospital of the Joint Logistics Support Force PLA Yunnan Kunming 650032 ChinaAnorectal Department The First People's Hospital of Longnan Longnan 742500 ChinaDepartment of Interventional Radiology Tangdu Hospital Fourth Military Medical University Xi'an City Shaanxi Province 710038 ChinaDepartment of General Surgery Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi 710038 ChinaDepartment of General Surgery Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi 710038 ChinaAbstract Gasdermin D (GSDMD)‐induced pyroptosis is associated with inflammatory disease. However, the role of GSDMD in acute pancreatitis (AP) is not yet fully elucidated. This study reveals that GSDMD serves two distinct functions in pancreatic acinar cells and macrophages. In acinar cells, GSDMD inhibits the synthesis of pancreatic enzyme by downregulating the expression of Prss1, Pnlip, and Amy1 via the inhibition of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 (RPS6)/eukaryotic translation initiation factor 4E‐binding protein 1 (4EBP1) pathway. Moreover, GSDMD induces pancreatic acinar cells to express mucin 1 (MUC1) by activating the nuclear factor kappa‐B (NF‐κB) pathway, which forms a barrier that prevents digestive enzyme‐mediated digestion. However, GSDMD promotes the secretion of inflammatory cytokines by macrophages during AP. In addition, GSDMD increases the infiltration of macrophages and neutrophils in AP and increases the proportion of Th1 and Th17 lymphocyte subsets in peripheral blood. However, in general, the harmful effect of GSDMD in AP outweighs its beneficial effect, and GSDMD knockout can effectively alleviate AP. These findings indicate that GSDMD may be a potential target for the treatment of AP; however, its dual effects need to be comprehensively considered.https://doi.org/10.1002/advs.202502412acute pancreatitisgasdermin Dmucin 1pyroptosistrypsin |
| spellingShingle | Chaoxu Liu Ning Liang Chen Wu Zhaoyan Qiu Qian Huang Xiaolong Wei Shurong Zhang Shuanghong Lei Tao Yang Gang Wang Qian Wang Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis Advanced Science acute pancreatitis gasdermin D mucin 1 pyroptosis trypsin |
| title | Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis |
| title_full | Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis |
| title_fullStr | Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis |
| title_full_unstemmed | Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis |
| title_short | Gasdermin D‐Mediated Pyroptosis Exerts Two Opposite Effects of Resisting Enzymatic Digestion and Expanding Inflammatory Response in Acute Pancreatitis |
| title_sort | gasdermin d mediated pyroptosis exerts two opposite effects of resisting enzymatic digestion and expanding inflammatory response in acute pancreatitis |
| topic | acute pancreatitis gasdermin D mucin 1 pyroptosis trypsin |
| url | https://doi.org/10.1002/advs.202502412 |
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