2. Academic Validation
  3. Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease

Vitamin B2 and B3 nutrigenomics reveals a therapy for NAXD disease

  • Cell. 2026 Apr 30;189(9):2648-2662.e19. doi: 10.1016/j.cell.2026.01.022.
Ankur Garg 1,  Skyler Y Blume 1,  Helen Huynh 2,  Alec M Barrios 1,  Onurkan O Karabulut 1,  Qian Zhao 3,  Ayush D Midha 4,  Adam W Turner 5,  B Vittorio Resnick 5,  Xuewen Chen 2,  Ayushi Agrawal 5,  JaeYeon Kim 6,  Liuji Chen 7,  Qitao Ran 8,  Alison M Ryan 9,  Reece C Larson 9,  Mina Negahban 5,  Sophia C K Nelson 5,  Andrew C Yang 5,  Michela Traglia 5,  Reuben Thomas 5,  Ramon Sun 9,  Mercedes Paredes 6,  M Ryan Corces 10,  Hening Lin 11,  Isha H Jain 12
Affiliations

Affiliations

  • 1 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 3 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Department of Medicine and Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
  • 4 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Medical Scientist Training Program, University of California, San Francisco, San Francisco CA 94143, USA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5 Gladstone Institutes, San Francisco, CA 94158, USA.
  • 6 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 7 Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229, USA.
  • 8 Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229, USA; South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
  • 9 Department of Biochemistry & Molecular Biology, College of Medicine, Center for Advanced Spatial Biomolecule Research, Evelyn F. and William L. McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
  • 10 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 11 Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA; Howard Hughes Medical Institute, Department of Medicine and Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
  • 12 Gladstone Institutes, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: [email protected].
PMID: 41747729 DOI: 10.1016/j.cell.2026.01.022
Abstract

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.

Keywords

CRISPR screens; NAD(H); NADH(X); NAXD; genomics; inborn errors of metabolism; metabolism; niacin; vitamin B3; vitamins.

Figures
Products