Nuclear NAD(+) promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation.

Nuclear NAD+ elevation during trained immunity directly binds KDM5A demethylase to inhibit H3K4me3 loss, sustaining promoter chromatin accessibility for stronger inflammatory gene responses on restimulation.

• Why it matters: Trained immunity depends on metabolic and epigenetic reprogramming, but the chromatin-level mechanism linking NAD+ metabolism to long-term innate immune memory was unclear.
• What they did: In mice, trained immunity induction increased nuclear NAD+; NAMPT deletion or pharmacologic inhibition impaired trained immunity and antitumor activity, while NMN supplementation rescued these defects in NAMPT-deficient and aged mice.
• The result: KDM5A functions as a nuclear NAD+ sensor that maintains H3K4me3 and accessibility at inflammatory promoters, and NAMPT-linked NAD+ metabolism is linked to an inflammatory tumor microenvironment in human myeloid cells.

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