Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation

Huanhuan Cai, Xueyuan Chen, Yan Liu, Yingbo Chen, Gechang Zhong, Xiaoyu Chen, Shuo Rong, Hao Zeng, Lin Zhang, Zelong Li, Aihua Liao, Xiangtai Zeng, Wei Xiong, Cihang Guo, Yanfang Zhu, Ke-Qiong Deng, Hong Ren, Huan Yan, Zeng Cai, Ke Xu, Li Zhou, Zhibing Lu (), Fubing Wang () and Shi Liu ()
Additional contact information
Huanhuan Cai: Zhongnan Hospital of Wuhan University
Xueyuan Chen: The Fifth Medical Center of Chinese PLA General Hospital
Yan Liu: The Fifth Medical Center of Chinese PLA General Hospital
Yingbo Chen: Wuhan University
Gechang Zhong: Wuhan University
Xiaoyu Chen: Wuhan University
Shuo Rong: Wuhan University
Hao Zeng: Wuhan University
Lin Zhang: Zhongnan Hospital of Wuhan University
Zelong Li: First Affiliated Hospital of Gannan Medical University
Aihua Liao: First Affiliated Hospital of Gannan Medical University
Xiangtai Zeng: First Affiliated Hospital of Gannan Medical University
Wei Xiong: Zhongnan Hospital of Wuhan University
Cihang Guo: Zhongnan Hospital of Wuhan University
Yanfang Zhu: Zhongnan Hospital of Wuhan University
Ke-Qiong Deng: Zhongnan Hospital of Wuhan University
Hong Ren: Affiliated Hospital to Shanghai Jiao Tong University School of Medicine
Huan Yan: Wuhan University
Zeng Cai: Wuhan University
Ke Xu: Wuhan University
Li Zhou: Wuhan University
Zhibing Lu: Zhongnan Hospital of Wuhan University
Fubing Wang: Chinese Academy of Medical Sciences
Shi Liu: Zhongnan Hospital of Wuhan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.

Date: 2025
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DOI: 10.1038/s41467-025-58563-2

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