MECHANISMS OF NICOTINAMIDE SECRETION IN ACTIVATED MACROPHAGES

Nicotinamide (NAM) is a key precursor in the NAD+ salvage pathway and a central metabolite in mammalian cells. While much is known about NAD+ biosynthesis, the cellular mechanisms underlying NAM transport remain poorly defined, particularly in terms of secretion. Preliminary data reveal that bone marrow-derived macrophages from mice, when stimulated with lipopolysaccharide (LPS), exhibit a paradoxical reduction in intracellular NAM levels and a marked increase in extracellular NAM, suggesting the existence of active secretion mechanisms that are upregulated under inflammatory conditions. Notably, these cells do not produce methylated NAM derivatives, such as M-NAM, reinforcing the hypothesis of direct NAM export, rather than its metabolic conversion. This project aims to identify membrane transporters involved in NAM secretion by integrating transcriptomic datasets from LPS-stimulated macrophages. Differentially expressed genes encoding membrane proteins will be analyzed for co-essentiality with NAD+ metabolic pathways and ranked based on network interaction analyses. By elucidating the molecular machinery responsible for NAM efflux in activated macrophages, this research seeks to uncover novel regulatory layers of NAD+ homeostasis with potential implications for therapeutic modulation of immune cell metabolism. This study aims to elucidate novel molecular mechanisms regulating macrophage bioenergetics and inflammatory signaling, while contributing to a broader understanding of NAD+ metabolism in physiological and pathological contexts. Identifying NAM transporters may uncover new therapeutic targets for inflammatory, metabolic, and age-related diseases.