RT Journal Article SR Electronic T1 Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101157 DO 10.26508/lsa.202101157 VO 5 IS 4 A1 Amy Tarangelo A1 Jason Rodencal A1 Joon Tae Kim A1 Leslie Magtanong A1 Jonathan Z Long A1 Scott J Dixon YR 2022 UL https://www.life-science-alliance.org/content/5/4/e202101157.abstract AB Nucleotide synthesis is a metabolically demanding process essential for DNA replication and other processes in the cell. Several anticancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR results in conservation of intracellular glutathione, limiting the accumulation of toxic lipid peroxides and preventing the onset of ferroptosis in response to cystine deprivation. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death.