Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease.

Vitamins are essential metabolites that must be obtained from external sources. In modern times, they have become widely available, leading to their ad hoc consumption. We developed a nutritional genomics framework to systematically identify monogenic diseases responsive to micronutrient modulation. Genome-wide CRISPR screens under varying vitamin B2 and B3 levels revealed dozens of candidate disease genes amenable to rescue by individual vitamins. In the vitamin B3 screen, NAD(P)HX dehydratase (NAXD) was the top hit; this enzyme repairs an aberrant, hydrated form of NADH (6-hydroxy-1,4,5,6-tetrahydronicotinamide-adenine dinucleotide [NADHX]), and its loss causes severe neurodevelopmental disease. In our Naxd knockout (KO) mouse, we observed NADHX accumulation, NAD+ depletion, and impaired serine biosynthesis in neonatal KO brains. Spatial metabolomics, single-nuclei RNA sequencing (snRNA-seq), and histology pinpointed cortical and brain endothelial cell vulnerability. Low-vitamin B3 diets accelerated pathology, whereas vitamin B3 supplementation extended lifespan by more than 40-fold. These findings establish a nutritional genomics framework and demonstrate the therapeutic potential of precision vitamin interventions.

• Publication year

  2026

• Venue

  Cell

• Publication date

  2026-02-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.cell.2026.01.022PMID 41747729PMCID PMC13008479
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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