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
  • 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.
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