Nicotinamide suppresses cytosolic DNA-Driven immunity independent of NAD+ via epigenetic modulation

Abstract

Dysregulation of cytosolic DNA-triggered IFN-I signaling is a key driver of autoimmune and autoinflammatory pathogenesis. Precise metabolic orchestration of cytokine signaling is critical for immune homeostasis, but the role of endogenous metabolites in fine-tuning IFN-I transcriptional output remains elusive. Here, we identify nicotinamide (NAM), a traditional NAD + precursor, as an immunosuppressor that dynamically accumulates upon cytosolic DNA stimulation and restrains IFN-I signaling independently of NAD + . Further study demonstrates that cytosolic DNA sensing specifically upregulates the NAD + hydrolase CD38, which mediates NAM accumulation through hydrolyzing NAD + . Mechanistic investigations reveal that NAM reduces the activating histone mark H3K4me3 at the IFNB promoter, thereby decreasing chromatin accessibility, impairing IRF3 recruitment, and ultimately suppressing IFNB transcription. Importantly, in vivo NAM administration dampens aberrant IFN-I signatures and alleviates autoimmune pathology in Trex1 ⁻/⁻ mice (a well-established model of IFN-I-driven autoimmunity). Collectively, our study uncovers a novel immunomodulatory function of NAM that is free from NAD + synthesis, delineates its epigenetic regulatory cascade on IFN-I signaling, and proposes the CD38-NAM axis as a therapeutic target for IFN-I-associated diseases.