Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect

Piao Luo; Qian Zhang; Tian-Yu Zhong; Jia-Yun Chen; Jun-Zhe Zhang; Ya Tian; Liu-Hai Zheng; Fan Yang; Ling-Yun Dai; Chang Zou; Zhi-Jie Li; Jing-Hua Liu; Ji-Gang Wang

doi:10.1186/s40779-022-00381-4

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Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect

RESEARCH | Updated：2023-03-23

- Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect
- Military Medical Research Vol. 10, Issue 1, Pages: 17-31(2023)
- Affiliations：
  
  1.Artemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing 100700 , China
  2.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515 , China
  3.Laboratory Medicine, the First Affiliated Hospital of Gannan Medical University, Ganzhou 341000 , Jiangxi, China
  4.Department of Geriatric Medicine, Shenzhen People’s Hospital, the Second Clinical Medical College, Jinan University and the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020 , Guangdong, China
  5.Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515 , China
  6.Center for Reproductive Medicine, Dongguan Maternal and Child Health Care Hospital, Southern Medical University, Dongguan 523125 , Guangdong, China
  7.Central People’s Hospital of Zhanjiang, Zhanjiang 524037 , Guangdong, China
- Author bio：
  
  * li.zhijie@szhospital.com;
  liujhua@smu.edu.cn;
  jgwang@icmm.ac.cn
- Funds：
- DOI：10.1186/s40779-022-00381-4
  CLC：
- Published：2023-02
- Accepted：
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Luo P, Zhang Q, Zhong TY, Chen JY, Zhang JZ, Tian Y, et al. Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect. Mil Med Res. 2022;9(1):22.
DOI：

Luo P, Zhang Q, Zhong TY, Chen JY, Zhang JZ, Tian Y, et al. Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect. Mil Med Res. 2022;9(1):22. DOI： 10.1186/s40779-022-00381-4.

摘要

Abstract

Background:

Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis.

Methods:

We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis

and the functional effects of such binding were explored through gene knockdown.

Results:

Cel protected mice from lethal endotoxemia and improved their survival with sepsis

and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS (

0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2)

inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein

reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA).

Conclusions:

Cel inhibits inflammation and the Warburg effect in sepsis

via

targeting PKM2 and HMGB1 protein.

关键词

Keywords

references

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