1. Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity
- Author
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Yongxiang Liu, Zifeng Wang, Huan Jin, Lei Cui, Bitao Huo, Chunyuan Xie, Jiahui Li, Honglu Ding, Huanling Zhang, Wenjing Xiong, Mengyun Li, Hongxia Zhang, Hui Guo, Chunwei Li, Tiantian Wang, Xiaojuan Wang, Wenzhuo He, Zining Wang, Jin-Xin Bei, Peng Huang, Jinyun Liu, and Xiaojun Xia
- Subjects
CP: Immunology ,CP: Cancer ,Biology (General) ,QH301-705.5 - Abstract
Summary: The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.
- Published
- 2024
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