Nicotinamide Riboside and Pyruvate Increase Anti-Inflammatory Pathways: Preclinical Findings

Synopsis

This study uncovered a previously unknown anti-inflammatory metabolite, homocysitaconate, produced through the interaction of homocysteine and itaconate during inflammation. The enzyme S-adenosyl-L-homocysteine hydrolase (AHCY)—which requires NAD+ for activity—catalyzes this reaction. During inflammation, levels of homocysitaconate rise dramatically (over 150-fold), and it acts as a metabolic brake to limit excessive immune activation. It works by binding to and inhibiting the pro-inflammatory enzyme methionyl-tRNA synthetase (MARS), which alters methionine metabolism, preventing harmful N-homocysteinylation of proteins. This mechanism helps promote NLRP3 ubiquitination, reducing inflammation. In animal models of sepsis, diet-induced inflammation, and colitis, increasing homocysitaconate levels had clear therapeutic benefits. Importantly, supplementing with nicotinamide riboside (NR) and pyruvate—both of which increase NAD+—enhanced AHCY activity and boosted homocysitaconate production, reducing inflammation through the MARS/NLRP3 pathway. These findings reveal a new NAD+-driven anti-inflammatory mechanism and suggest NR supplementation could help regulate inflammatory diseases by promoting beneficial metabolic feedback loops.

Journal

Cell Metabolism