Nicotinic acid riboside (NAR)

Nicotinic acid riboside (NAR, NaR) is the beta-glycosidic nucleoside of nicotinic acid and D-ribofuranose and a physiological precursor of nicotinamide adenine dinucleotide (NAD+) that is metabolized through the Preiss-Handler branch of the NAD+ salvage pathway. First characterized as a substrate of the nicotinamide riboside kinases (NRK1 and NRK2) in the seminal Bieganowski and Brenner (2004) report that established NRK-dependent NAD+ biosynthesis in fungi and humans, NAR was subsequently demonstrated by Tempel et al. (2007) to be phosphorylated by human NRK1 and NRK2 with catalytic efficiency comparable to that observed for nicotinamide riboside (NR), reflecting steric rather than electrostatic substrate discrimination at the enzyme active site. The Kulikova et al. (2015) study in the Journal of Biological Chemistry established NAR as an authentic intermediate of human NAD+ metabolism by demonstrating that cytosolic 5-nucleotidases CN-II and CN-III catalyze the dephosphorylation of nicotinic acid mononucleotide (NAMN) to NAR, that human cells release NAR into the extracellular space at concentrations sufficient to sustain the viability of neighboring NAPRT-deficient cells, and that submicromolar NAR concentrations support cell survival more efficiently than equimolar NR in FK866-treated hepatoma models.

The biological significance of NAR was substantially advanced by the Jang, Yang, and colleagues (2025) publication in Cell Metabolism, which identified cytosolic 5-nucleotidase II (NT5C2) as the principal hepatic NAR-producing enzyme and characterized a liver-to-kidney NAD+ relay in which the liver generates and exports NAR to the circulation, the kidneys import NAR via NRK1-dependent phosphorylation, synthesize NAD+, and release nicotinamide back to the systemic pool. This inter-organ relay was demonstrated by the approximately 30-fold accumulation of hepatic NaR in liver-specific NMNAT1 knockout mice and by isotope tracing showing that circulating NaR contributed 100 percent of kidney nicotinic acid adenine dinucleotide (NaAD) and approximately 75 percent of kidney NAD+ in these animals. Serum NaR levels declined significantly in aged (25-month) mice compared to young (3-month) controls, and oral NaR supplementation at 1 g/L in drinking water for two weeks restored multi-organ NAD+ (kidney, liver, heart, pancreas), reversed kidney ATP depletion, suppressed kidney injury markers (Kim1, Fgl2), reduced macrophage infiltration, and decreased the urine albumin-to-creatinine ratio.

Cellular transport of NAR is mediated by equilibrative nucleoside transporters ENT1, ENT2, and ENT4, with the inward flux dependent on intracellular metabolic clearance through NRK2-catalyzed phosphorylation, as demonstrated by Kropotov et al. (2021). Concentrative nucleoside transporter CNT3 provides a secondary, modest uptake pathway. Unlike nicotinic acid (niacin), NAR does not activate the GPR109A (HCA2) receptor and is therefore not expected to produce the prostaglandin-mediated cutaneous flushing that limits high-dose niacin supplementation. Unlike nicotinamide riboside, NAR enters the deamidated (Preiss-Handler) branch of NAD+ biosynthesis, requiring amidation by glutamine-dependent NAD+ synthetase (NADSYN) for the final conversion of NaAD to NAD+, a step that may confer tissue-specific efficacy dependent on local NADSYN expression.

This monograph reviews the chemistry, structural identification, and synthesis of NAR; the enzymatic generation by 5-nucleotidases and phosphorylation by NRK1 and NRK2; the Preiss-Handler salvage pathway and the liver-kidney NAD+ relay; the pharmacokinetics and transport; the preclinical pharmacology in aging, renal protection, and metabolic models; the emerging clinical and translational evidence base; sourcing and quality verification; reconstitution and handling; stack interactions; adverse-event considerations; and a structured comparative assessment of five NAD+ precursor candidates (nicotinamide riboside, nicotinamide mononucleotide, nicotinic acid, nicotinamide, and tryptophan) against NAR on five competency standards. The compound is not approved as a pharmaceutical by any regulatory authority. It is available as a research-grade preparation; investigators should obtain analytical confirmation of identity and purity on every lot.