{"title":"ADP-ribose induces neuronal ferroptosis through ENT2-mediated nucleotide rewiring.","authors":"Haoqi Ni, Yingying He, Qiao Ye, Peng Cui, Jieyuan Yuan, Guoqing Lv, Huiyan Lei, Qian Wang, Feng Wang, Qichuan ZhuGe, Baodong Chen, Ling Liang, Yong Zhang, Lin Yuan","doi":"10.1038/s41589-026-02355-2","DOIUrl":"https://doi.org/10.1038/s41589-026-02355-2","url":null,"abstract":"<p><p>Excessive nicotinamide adenine dinucleotide (NAD<sup>+</sup>) consumption fuels neurological pathogenesis, yet the limited benefit of NAD<sup>+</sup> supplementation hints at unresolved toxicity from its catabolism. Here, we identify ADP-ribose, a neglected NAD<sup>+</sup> 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<sup>+</sup> hyperconsumption.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149288031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Putting the Warburg effect in reverse.","authors":"Valentin Cracan","doi":"10.1038/s41589-026-02343-6","DOIUrl":"https://doi.org/10.1038/s41589-026-02343-6","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149245408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dina Y. Bass, Ekaterina S. Potekhina, Alexander V. Ivanenko, Aleksandr A. Moshchenko, Dmitry A. Korzhenevskiy, Alexey M. Nesterenko, Evgeny K. Shevchenko, Anastasia E. Karnaeva, Natalia F. Zakirova, Alexander V. Ivanov, Liubov E. Shimolina, Marina V. Shirmanova, Olga V. Lyang, Olga I. Patsap, Olga M. Kudryashova, Guzel R. Gazizova, Elena I. Shagimardanova, Sofia S. Mariasina, Vasiliy A. Ivlev, Ivan Bogeski, Oleg A. Gusev, Vsevolod V. Belousov
{"title":"Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells","authors":"Dina Y. Bass, Ekaterina S. Potekhina, Alexander V. Ivanenko, Aleksandr A. Moshchenko, Dmitry A. Korzhenevskiy, Alexey M. Nesterenko, Evgeny K. Shevchenko, Anastasia E. Karnaeva, Natalia F. Zakirova, Alexander V. Ivanov, Liubov E. Shimolina, Marina V. Shirmanova, Olga V. Lyang, Olga I. Patsap, Olga M. Kudryashova, Guzel R. Gazizova, Elena I. Shagimardanova, Sofia S. Mariasina, Vasiliy A. Ivlev, Ivan Bogeski, Oleg A. Gusev, Vsevolod V. Belousov","doi":"10.1038/s41589-026-02350-7","DOIUrl":"https://doi.org/10.1038/s41589-026-02350-7","url":null,"abstract":"Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"13 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149241635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Finding signal in the noise","authors":"Irene Serrano","doi":"10.1038/s41589-026-02360-5","DOIUrl":"10.1038/s41589-026-02360-5","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1703-1703"},"PeriodicalIF":15.8,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Sensing red light","authors":"Huijuan Guo","doi":"10.1038/s41589-026-02363-2","DOIUrl":"10.1038/s41589-026-02363-2","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1704-1704"},"PeriodicalIF":15.8,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Being N sync","authors":"Gene Chong","doi":"10.1038/s41589-026-02361-4","DOIUrl":"10.1038/s41589-026-02361-4","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1703-1703"},"PeriodicalIF":15.8,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachel E Hayward, Raymond F Berkeley, Zijian Gao, Maximilian Garhammer, Marc A Morizono, Evert Njomen, Haoxin Li, Kristen E DeMeester, Victor Cociorva, Mark A Herzik, F Ulrich Hartl, Bruno Melillo, Benjamin F Cravatt
{"title":"Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.","authors":"Rachel E Hayward, Raymond F Berkeley, Zijian Gao, Maximilian Garhammer, Marc A Morizono, Evert Njomen, Haoxin Li, Kristen E DeMeester, Victor Cociorva, Mark A Herzik, F Ulrich Hartl, Bruno Melillo, Benjamin F Cravatt","doi":"10.1038/s41589-026-02348-1","DOIUrl":"10.1038/s41589-026-02348-1","url":null,"abstract":"<p><p>Activity-based protein profiling has identified hundreds of human proteins from diverse classes that react at cysteine residues with stereochemically defined electrophilic compounds (stereoprobes). The structure-activity relationships underlying these stereoprobe-protein interactions, however, remain poorly understood. Here, we show that the protein interaction landscape of tryptoline acrylamide stereoprobes can be profoundly altered by structural modifications distal to the acrylamide reactive group. Most stereoprobe liganding events occurred at nonorthosteric sites and evaded assignment by the machine learning-based cofolding model Boltz-2, which instead tended to misplace stereoprobes in orthosteric pockets (an outcome we term 'orthostery burnout'). We found that stereoprobes reacting with C124 in the nucleotide exchange factor GRPEL1 disrupt interactions with the mitochondrial HSP70 chaperone HSPA9/mortalin, leading to impairments in mitochondrial protein import and mitophagy induction. Our results highlight tryptoline acrylamides as a versatile source of covalent ligands targeting nonorthosteric sites on proteins, including tool compounds that perturb the mitochondrial HSP70 chaperone system.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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