Inhibition of mPTP and GSDME-mediated pyroptosis alleviates lung injury in septic mice

  • Eur J Pharmacol. 2026 Jun 15:1027:178967. doi: 10.1016/j.ejphar.2026.178967.
Na Lu  1 ,  Meng-Jie Yu  2 ,  Rui Zhang  3 ,  Zhao-Fei Meng  4 ,  Hong-Wei Ye  2 ,  Ying Yu  2 ,  Qin Gao  5 ,  Jun-Feng Hu  6
Affiliations
  • 1. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Clinical Research Center for Respiratory Disease (tumor) in Anhui Province, Bengbu, Anhui, 233000, PR China; Department of Respiratory, Linyi Central Hospital, Yishui, Shandong, 276400, PR China.
  • 2. Department of Physiology, Bengbu Medical University, Bengbu, Anhui, 233000, PR China; Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui, 233000, PR China.
  • 3. Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui, 233000, PR China; College of Life Sciences, Bengbu Medical University, Bengbu, Anhui, 233000, PR China.
  • 4. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Clinical Research Center for Respiratory Disease (tumor) in Anhui Province, Bengbu, Anhui, 233000, PR China.
  • 5. Department of Physiology, Bengbu Medical University, Bengbu, Anhui, 233000, PR China; Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical University, Bengbu, Anhui, 233000, PR China. Electronic address: [email protected].
  • 6. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Bengbu Medical University, Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Clinical Research Center for Respiratory Disease (tumor) in Anhui Province, Bengbu, Anhui, 233000, PR China. Electronic address: [email protected].
PMID: 42134760 DOI: 10.1016/j.ejphar.2026.178967
Abstract

Objective: To explore the role of mitochondrial permeability transition pore (mPTP) and gasdermin E (GSDME) - mediated Pyroptosis in septic lung injury in mice model.

Methods: Adult male c57BL/6J mice were randomly assigned with 10 mice in each group. Sepsis model was established by cecal ligation and puncture (CLP) operation. Alisporivir (AL) was used to inhibit the opening of mPTP, plumbagin (PL) was used to open mPTP. Knockdown or overexpression of GSDME were done by Adeno associated virus 6 (AAV 6). The changes of lung tissue, ultrastructure, Reactive Oxygen Species (ROS), GSDME-mediated Pyroptosis related proteins, inflammatory factors and mitochondrial function were detected.

Results: Compared with Sham group, the aggravating of lung injury, mitochondrial dysfunction, oxidative stress and inflammatory reaction were shown in CLP and GSDME high-expression groups, and the opening of mPTP, the mRNA levels of Pyroptosis related genes were increased, the expressions of Pyroptosis related proteins were increased. After inhibiting mPTP opening by AL or knockdown GSDME respectively, septic lung injury was alleviated, mitochondrial function was improved, oxidative stress and inflammatory response were reduced, the mRNA levels of GSDME and Caspase-3 were decreased, the protein expressions of GSDME, Caspase-3, IL-1β and IL-18 were reduced. In knockdown GSDME group, the application of PL to open mPTP still played the protective role.

Conclusion: Inhibiting mPTP opening or GSDME-mediated Pyroptosis both alleviated septic lung injury. The mPTP is the upstream of GSDME, GSDME-N can also positively promote mPTP opening, mPTP and GSDME regulates each Other in the GSDME-mediated Pyroptosis pathway.

Keywords
GSDME; Mitochondrial permeability transition pore; Pyroptosis; Septic lung injury.
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