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

Luo，Piao1,2; Zhang，Qian1,2; Zhong，Tian Yu3; Chen，Jia Yun1; Zhang，Jun Zhe1; Tian，Ya1; Zheng，Liu Hai4; Yang，Fan4; Dai，Ling Yun4; Zou，Chang2; Li，Zhi Jie4; Liu，Jing Hua5; Wang，Ji Gang1,2,3,4,6,7

2022-12-01

10.1186/s40779-022-00381-4

Military Medical Research   Impact Factor & Quartile

2095-7467

2054-9369

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 (P < 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). Conclusion: Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.

Aerobic glycolysis Celastrol High mobility group box 1 Pyruvate kinase M2 Sepsis

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English

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WOS:000800807300001

2-s2.0-85130323863

Scopus

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,Jiangxi,341000,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,Guangdong,518020,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,Guangdong,523125,China
7.Central People’s Hospital of Zhanjiang,Zhanjiang,Guangdong,524037,China

Luo，Piao,Zhang，Qian,Zhong，Tian Yu,et al. Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect[J]. Military Medical Research,2022,9(1).

Luo，Piao.,Zhang，Qian.,Zhong，Tian Yu.,Chen，Jia Yun.,Zhang，Jun Zhe.,...&Wang，Ji Gang.(2022).Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect.Military Medical Research,9(1).

Luo，Piao,et al."Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect".Military Medical Research 9.1(2022).