Excessive nicotinamide adenine dinucleotide (NAD+) consumption fuels neurological pathogenesis, yet the limited benefit of NAD+ supplementation hints at unresolved toxicity from its catabolism. Here, we identify ADP-ribose, a neglected NAD+ catabolite generated by poly(ADP-ribose) polymerase 1 (PARP1) and poly(ADP-ribose) glycohydrolase, as an inducer of neuronal ferroptosis through nucleotide metabolic rewiring. We discovered that extracellular ADP-ribose directly binds and inhibits the nucleoside transporter equilibrative nucleoside transporter 2 (ENT2; SLC29A2), suppressing nucleotide salvage and driving compensatory hyperactivation of de novo purine and pyrimidine biosynthesis.
This metabolic rerouting engages xanthine oxidase (XO) and dihydroorotate dehydrogenase (DHODH) to unleash superoxide bursts, triggering lipid peroxidation and ferroptotic neuronal death. ADP-ribose accumulates across neurological disease models and its acute administration recapitulates ferroptotic neurodegeneration in vivo. Targeting ADP-ribose signaling through PARP1 knockdown, NUDT9-mediated hydrolysis or dual XO/DHODH inhibition rescues delayed cognitive deficits in intracerebral hemorrhage models.
These findings define the ADP-ribose–ENT2 axis as a metabolic driver of neuronal ferroptosis and reveal a druggable vulnerability in disorders marked by NAD+ hyperconsumption. This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout All data are available in the paper. MS data were deposited to ProteomeXchange under dataset identifiers PXD053136 and PXD053139.
Newly generated plasmids and viral constructs are available from the corresponding author upon reasonable request. Source data are provided with this paper. Y., Ugurbil, K. & Chen, W.
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