Science Immunology· 2026Q1
Nuclear NAD + promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation
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- Q1SCImago
- 2026year
Short summary
Nuclear NAD+ directly inhibits KDM5A demethylase activity, sustaining H3K4me3 levels and chromatin accessibility at inflammatory gene promoters to enhance innate immune memory.
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Key points
- Nuclear NAD+ levels increase during trained immunity and directly inhibit KDM5A demethylase activity.
- Inhibition of KDM5A sustains H3K4me3 and chromatin accessibility at inflammatory gene promoters, establishing immune memory.
- Impairing NAD+ synthesis (via NAMPT inhibition) reduces trained immunity and antitumor activity.
- NMN supplementation rescues trained immunity and antitumor activity in NAMPT-deficient and aged mice.
- NAMPT expression in human myeloid cells correlates with an inflammatory tumor microenvironment.
AI-generated from the title and abstract; the full text is not read.
Abstract
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.
The authors' abstract, as published at the source. Science Immunology, 2026 · DOI ↗
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ImmunologyImmunology and Microbiology