期刊
ENVIRONMENTAL POLLUTION
卷 295, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.envpol.2021.118708
关键词
Benzene; PKM2; Glycolysis; Inflammation; Acetylation; Hematotoxicity
资金
- National Natural Science Foundation of China [82073520, 81773397]
- Beijing Natural Science Foundation Program [KZ201810025032]
- Scientific Research Key Program of Beijing Municipal Commission of Education [KZ201810025032]
- Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan [CITTCD 20170323]
This study reveals the involvement of the PKM2/pStat3/IL-17A axis in the hematotoxicity of benzene and highlights the potential therapeutic implications of targeting PKM2 in hematologic diseases.
Benzene is a common environmental carcinogen that induces leukemia. Studies suggest that metabolic disorder has a relationship with the toxicity of benzene. Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis. However, the upstream and downstream regulatory mechanisms of PKM2 in benzene-induced hematotoxicity and the therapeutic effects of targeting PKM2 in vivo are unclear. This study aims to provide insights into the new mechanism of benzene-induced hematotoxicity and reveal the therapeutic significance of targeting PKM2. Herein, we demonstrated that PKM2-dependent glycolysis contributes to benzene-induced hematotoxicity by regulating inflammation reaction. Mechanistically, acetylated proteomics revealed that 1,4-benzoquinone (1,4-BQ) induced acetylation of PKM2 at position K66, and this modification contributed to the increase of PKM2 expression and can be inhibited by inhibition of acetyltransferase GCN5. Meanwhile, the elevated PKM2 was shown to prompt the activation of nuclear phosphorylated Stat3 (p-Stat3) and IL17A. Clinically, pharmacological inhibition of PKM2 alleviated the blood toxicity induced by benzene, which was mainly characterized by an increase in routine blood parameters and improvement of hematopoietic imbalance. Besides, elevated PKM2 is a promising biomarker in people occupationally exposed to benzene. Overall, we identified PKM2/pStat3/IL-17A axis participates in the hematotoxicity of benzene, and targeting PKM2 has certain therapeutic implications in hematologic diseases.
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