ADP-ribose induces neuronal ferroptosis through ENT2-mediated nucleotide rewiring.

ADP-ribose induces neuronal ferroptosis by directly binding and inhibiting ENT2 (SLC29A2), suppressing nucleotide salvage and triggering compensatory de novo purine and pyrimidine biosynthesis.

• Why it matters: NAD+ hyperconsumption in neurological disease is linked to toxicity that NAD+ supplementation alone does not resolve, leaving NAD+ catabolite–driven mechanisms unclear.
• What they did: The study shows extracellular ADP-ribose binds and inhibits ENT2, causing nucleotide metabolic rewiring that engages xanthine oxidase and DHODH to generate superoxide bursts and lipid peroxidation.
• The result: ADP-ribose accumulates across neurological disease models, and acute administration recapitulates ferroptotic neurodegeneration in vivo; PARP1 knockdown, NUDT9-mediated hydrolysis, or dual XO/DHODH inhibition rescues delayed cognitive deficits in intracerebral hemorrhage models.