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

Nenghua Zhou; Yun Zhang; Yan Jiao; Jinshan Nan; Anjie Xia; Bo Mu; Guifeng Lin; Xun Li; Shanshan Zhang; Shengyong Yang; Linli Li

doi:10.1016/j.intimp.2023.111314

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. Epub 2023 Dec 10.

Authors

Nenghua Zhou¹, Yun Zhang², Yan Jiao³, Jinshan Nan⁴, Anjie Xia², Bo Mu⁵, Guifeng Lin⁴, Xun Li², Shanshan Zhang⁴, Shengyong Yang⁶, Linli Li⁷

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: yangsy@scu.edu.cn.
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: lilinli@scu.edu.cn.

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.

MeSH terms

Caspase 1 / metabolism
Humans
Inflammasomes* / metabolism
Inflammation / metabolism
Interleukin-1beta / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
Pyroptosis
Signal Transduction

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
Inflammasomes
Caspase 1
Interleukin-1beta