ADP-ribose triggers neuronal ferroptosis via metabolic orchestrating

The depletion of NAD is intimately linked to neurodegenerative diseases and aging. Excessive activation of NAD+-consuming enzymes that hydrolyze NAD to ADP-ribose and nicotinamide is closely related to neurodegenerative diseases. However, supplementation of NAD or its precursors failed to show any benefits for most patients. The molecular mechanisms underlying this are largely undefined. Here we show that ADP-ribose, as an endogenous NAD metabolite, triggers neuronal cell death by glutathione-independent ferroptosis. The neuronal cells in both the hippocampus and cerebral cortex were severely reduced under the treatment of ADP-ribose in mice. Intracellular ADP-ribose, an endogenous inhibitor of NAD-cofactor enzymes, but not NAD-consuming enzymes, is an accelerator of ferroptosis by blocking the catabolism of lipid peroxidation. Furthermore, the extracellular ADP-ribose directly binds to membrane surface nucleoside transporter ENT1 to orchestrate purine and pyrimidine metabolism. ENT1-hypoxanthine axis and glutamine-dihydroorotate-quinone pathway are independent and intersecting, which is specifically mobilized by ADP-ribose to trigger ferroptosis. Precisely because of it, we find that the neuronal death by ADP-ribose can be rescued by XO and DHODH inhibitors. Moreover, endogenous ADP-ribose levels are increased on oxidative stress and PROTAC of PARP1 maintain neuronal survival under these circumstances. We provide evidence that ADP-ribose is a key metabolite that is used for disease diagnosis and drug target. Our analyses uncover new molecular links between NAD metabolism and ferroptosis in the regulation of neuronal death, thus suggesting new strategies for the prevention and treatment of neurodegenerative diseases.