Nuclear NAD + promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation
Huan Jin, Zining Wang, Yongxiang Liu, Zifeng Wang, Mengyun Li, Ju Xue, Yiqun Zhang, Tiantian Yu, Shoujie Wang, Bitao Huo, Chunwei Li, Xiaojuan Wang, Ruhui Yao, Huanling Zhang, Jiahong Yi, Yanxun Lin, Lei Cui, Hui Guo, Zixuan Guo, Ling Zhang, Chaoyun Pan, Xuetong Shen, Gelin Wang, Gaofeng Fan, Zhiming Wu, Jing Tan, Song Gao, Jin-Xin Bei, Peng Huang, Jinyun Liu, Xiaojun XiaTrained immunity is tightly regulated by metabolic and epigenetic reprogramming, yet how these changes are orchestrated at the chromatin level to establish long-term innate immune memory is not fully understood. Here, we show that induction of trained immunity elevates nuclear levels of nicotinamide adenine dinucleotide (NAD + ), which directly binds to KDM5A demethylase and inhibits its activity, thereby sustaining H3K4me3 (histone H3 lysine 4 trimethylation) levels and chromatin accessibility at inflammatory gene promoters to enhance “memory” responsiveness upon restimulation. Genetic deletion or pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD + synthesis, impaired trained immunity and associated antitumor activity. Nicotinamide mononucleotide (NMN) supplementation rescued defective trained immunity–mediated antitumor activity in NAMPT-deficient and aged mice. In human cancer, NAMPT expression in myeloid cells correlated with an inflammatory tumor microenvironment. Our findings identify KDM5A as a nuclear NAD + sensor that orchestrates histone methylation and chromatin accessibility required for trained immunity.