Nuclear NAD + promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation
Trained 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.
Authors
- Song Gao (ORCID: https://orcid.org/0000-0001-7427-6681)
- Xiaojun Xia (ORCID: https://orcid.org/0000-0003-4444-7472)
- Shen Xuetong (ORCID: https://orcid.org/0000-0002-4267-5298)
- Huanling Zhang (ORCID: https://orcid.org/0009-0004-1194-1188)
- Gelin Wang (ORCID: https://orcid.org/0000-0002-8162-9446)
- Jing Ying Tan (ORCID: https://orcid.org/0000-0002-4605-4624)
- Jiahong Yi (ORCID: https://orcid.org/0000-0002-7665-7258)
- Chaoyun Pan (ORCID: https://orcid.org/0000-0002-4255-9318)
- Zining Wang (ORCID: https://orcid.org/0000-0002-0087-2453)
- Jin‐Xin Bei (ORCID: https://orcid.org/0000-0003-1333-407X)
- Bitao Huo
- Yiqun Zhang (ORCID: https://orcid.org/0009-0000-5811-4439)
- Ling Zhang (ORCID: https://orcid.org/0000-0002-8308-6553)
- Peng Huang (ORCID: https://orcid.org/0000-0002-2152-9152)
- Zifeng Wang (ORCID: https://orcid.org/0000-0001-7400-5224)
- Ju Xue
- Gaofeng Fan (ORCID: https://orcid.org/0009-0009-1445-4832)
- Huan Jin (ORCID: https://orcid.org/0009-0003-4935-3704)
- Lei Cui (ORCID: https://orcid.org/0000-0001-7763-5205)
- Jinyun Liu (ORCID: https://orcid.org/0000-0002-4763-2684)
- Shoujie Wang
- Mengyun Li (ORCID: https://orcid.org/0000-0002-1889-6306)
- Ruhui Yao
- TianTian Yu
- Yongxiang Liu (ORCID: https://orcid.org/0009-0002-4468-1314)
- Zhiming Wu
- Hui Guo
- Zixuan Guo
- Yanxun Lin
- Xiaojuan Wang
- Chunwei Li
Institutions
- Tongji University (CN)
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Inner Mongolia University (CN)
- ShanghaiTech University (CN)
- Shanghai Ninth People's Hospital (CN)
- Fifth Affiliated Hospital of Sun Yat-sen University (CN)
- Shanghai Sunshine Rehabilitation Center (CN)
- Sun Yat-sen University Cancer Center (CN)
- State Key Laboratory of Oncology in South China (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1126/sciimmunol.aea5625
- Citations
- 1
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 2.64
Funders
- National Natural Science Foundation of China