2. Academic Validation
  3. Discovery of a novel pyroptosis inhibitor acting though modulating glutathionylation to suppress NLRP3-related signal pathway

Discovery of a novel pyroptosis inhibitor acting though modulating glutathionylation to suppress NLRP3-related signal pathway

  • Int Immunopharmacol. 2024 Jan 25:127:111314. doi: 10.1016/j.intimp.2023.111314.
Nenghua Zhou 1,  Yun Zhang 2,  Yan Jiao 3,  Jinshan Nan 4,  Anjie Xia 2,  Bo Mu 5,  Guifeng Lin 4,  Xun Li 2,  Shanshan Zhang 4,  Shengyong Yang 6,  Linli Li 7
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 2 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Ophthalmology and Macular Disease Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Laboratory of Anaesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu China.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Basic Medical College of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].
  • 7 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 38081102 DOI: 10.1016/j.intimp.2023.111314
Abstract

Pyroptosis is a proinflammatory type of regulated cell death and has been involved in many pathological processes. Inhibition of Pyroptosis is thought to be a promising strategy for the treatment of related diseases. Here, we performed a phenotypic screening against NLRP3-dependent Pyroptosis and obtained the novel compound N77 after structure optimization. N77 showed a half-maximal effective concentration (EC50) of 0.070 ± 0.008 μM against cell Pyroptosis induced by nigericin, and exhibited a remarkable ability to prevent NLRP3-dependent inflammasome activation and the release of IL-1β. Chemical proteomics revealed the biological target of N77 to be glutathione-S-transferase Mu 1 (GSTM1); our mechanism of action studies indicated that GSTM1 might act as a negative regulator of NLRP3 inflammasome activation by modulating the glutathionylation of Caspase-1. In vivo, N77 substantially alleviated the inflammatory reaction in a pyroptosis-related acute keratitis model. Overall, we identified a novel Pyroptosis Inhibitor and revealed a new regulatory mechanism of Pyroptosis. Our findings suggest an alternative potential therapeutic strategy for pyroptosis-related diseases.

Keywords

Acute keratitis; NLRP3 inflammasome; Pyroptosis; Pyroptosis inhibitor; Target identification; glutathione-S-transferase.

Figures
Products