Histone Deacetylase Inhibitor (SAHA) Reduces Mortality in an Endotoxemia Mouse Model by Suppressing Glycolysis

GND
1331100887
Zugehörigkeit
School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
Wu, Yunchen;
Zugehörigkeit
School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
He, Yudan;
Zugehörigkeit
School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
Liu, Chen;
GND
1331101107
Zugehörigkeit
Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07745 Jena, Germany
Ehle, Charlotte;
GND
1166868818
Zugehörigkeit
Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07745 Jena, Germany
Iyer-Bierhoff, Aishwarya;
Zugehörigkeit
School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
Liu, Bing;
GND
1211647552
ORCID
0009-0003-8937-6089
Zugehörigkeit
Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, 07745 Jena, Germany
Heinzel, Thorsten;
ORCID
0000-0003-0777-2196
Zugehörigkeit
School of Basic Medical Sciences, Shenzhen University, Shenzhen 518055, China
Xing, Shaojun

Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose significant challenges in sepsis treatment. Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been proposed as potent anti-inflammatory agents for treating inflammatory diseases. However, the underlying mechanisms of sepsis treatment remain poorly understood. In this study, we investigated the effects of SAHA treatment in the lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the early stages of the systemic inflammation of sepsis. Our results demonstrate a reduced inflammatory mediator secretion and improved survival rates in mice. Using quantitative acetylomics, we found that SAHA administration increases the acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages (BMDMs) show that SAHA administration reduced oxidative stress and extracellular ATP concentrations, ultimately blunting inflammasome activation. Overall, our study provides insights into the mechanism underlying SAHA’s therapeutic effects in sepsis treatment and highlights LDHA as a potential target for developing novel sepsis treatment.

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