{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:28:50Z","timestamp":1784896130932,"version":"3.55.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1S02017N"],"award-info":[{"award-number":["1S02017N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["EOS MODEL-IDI 30826052"],"award-info":[{"award-number":["EOS MODEL-IDI 30826052"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G.0E04.16N"],"award-info":[{"award-number":["G.0E04.16N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G.0C76.18N"],"award-info":[{"award-number":["G.0C76.18N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G.0B96.20N"],"award-info":[{"award-number":["G.0B96.20N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["12T9118N"],"award-info":[{"award-number":["12T9118N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004727","name":"Vlaams Instituut voor Biotechnologie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004727","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004385","name":"Universiteit Gent","doi-asserted-by":"publisher","award":["iBOF ATLANTIS"],"award-info":[{"award-number":["iBOF ATLANTIS"]}],"id":[{"id":"10.13039\/501100004385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["AI144400"],"award-info":[{"award-number":["AI144400"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["AI124049"],"award-info":[{"award-number":["AI124049"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"U.S. Department of Health & Human Services | National Institutes of Health","doi-asserted-by":"publisher","award":["AI144400"],"award-info":[{"award-number":["AI144400"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Butylate hydroxyanisole (BHA) is a synthetic phenol that is widely utilized as a preservative by the food and cosmetic industries. The antioxidant properties of BHA are also frequently used by scientists to claim the implication of reactive oxygen species (ROS) in various cellular processes, including cell death. We report on the surprising finding that BHA functions as a direct inhibitor of RIPK1, a major signaling hub downstream of several immune receptors. Our in silico analysis predicts binding of 3-BHA, but not 2-BHA, to RIPK1 in an inactive DLG-out\/Glu-out conformation, similar to the binding of the type III inhibitor Nec-1s to RIPK1. This predicted superior inhibitory capacity of 3-BHA over 2-BHA was confirmed in cells and using in vitro kinase assays. We demonstrate that the reported protective effect of BHA against tumor necrosis factor (TNF)-induced necroptotic death does not originate from ROS scavenging but instead from direct RIPK1 enzymatic inhibition, a finding that most probably extends to other reported effects of BHA. Accordingly, we show that BHA not only protects cells against RIPK1-mediated necroptosis but also against RIPK1 kinase-dependent apoptosis. We found that BHA treatment completely inhibits basal and induced RIPK1 enzymatic activity in cells, monitored at the level of TNFR1 complex I under apoptotic conditions or in the cytosol under necroptosis. Finally, we show that oral administration of BHA protects mice from RIPK1 kinase-dependent lethality caused by TNF injection, a model of systemic inflammatory response syndrome. In conclusion, our results demonstrate that BHA can no longer be used as a strict antioxidant and that new functions of RIPK1 may emerge from previously reported effects of BHA.<\/jats:p>","DOI":"10.1038\/s41419-021-03994-0","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T05:02:56Z","timestamp":1626238976000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Antioxidant and food additive BHA prevents TNF cytotoxicity by acting as a direct RIPK1 inhibitor"],"prefix":"10.1038","volume":"12","author":[{"given":"Tom","family":"Delanghe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Huyghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungheon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2527-1101","authenticated-orcid":false,"given":"Dario","family":"Priem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samya","family":"Van Coillie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sze Men","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-8822","authenticated-orcid":false,"given":"Peter","family":"Vandenabeele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Degterev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Cuny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Dondelinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9000-0626","authenticated-orcid":false,"given":"Mathieu J. M.","family":"Bertrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"3994_CR1","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3109\/10915818409021273","volume":"3","author":"J Busch","year":"1984","unstructured":"Busch J. Final report on the safety assessment of butylated hydroxyanisole. J Am Coll Toxicol. 1984;3:83\u2013146.","journal-title":"J Am Coll Toxicol"},{"key":"3994_CR2","first-page":"E50","volume":"60","author":"A Panico","year":"2019","unstructured":"Panico A, Serio F, Bagordo F, Grassi T, Idolo A, DE Giorgi M, et al. Skin safety and health prevention: an overview of chemicals in cosmetic products. J Prev Med Hyg. 2019;60:E50.","journal-title":"J Prev Med Hyg"},{"key":"3994_CR3","doi-asserted-by":"crossref","unstructured":"Rychen G, Aquilina G, Azimonti G, Bampidis V, de Lourdes Bastos M, Bories G, et al. Safety and efficacy of butylated hydroxyanisole (BHA) as a feed additive for all animal species. EFSA J. 2018;16:e05215.","DOI":"10.2903\/j.efsa.2018.5215"},{"key":"3994_CR4","doi-asserted-by":"publisher","first-page":"8115","DOI":"10.1073\/pnas.92.18.8115","volume":"92","author":"V Goossens","year":"1995","unstructured":"Goossens V, Grooten J, de Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA. 1995;92:8115\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3994_CR5","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1084\/jem.187.9.1477","volume":"187","author":"D Vercammen","year":"1998","unstructured":"Vercammen D, Beyaert R, Denecker G, Goossens V, van Loo G, Declercq W, et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med. 1998;187:1477\u201385.","journal-title":"J Exp Med"},{"key":"3994_CR6","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1038\/cdd.2009.184","volume":"17","author":"T vanden Berghe","year":"2010","unstructured":"vanden Berghe T, Vanlangenakker N, Parthoens E, Deckers W, Devos M, Festjens N, et al. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ. 2010;17:922\u201330.","journal-title":"Cell Death Differ"},{"key":"3994_CR7","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/cdd.2010.138","volume":"18","author":"N Vanlangenakker","year":"2011","unstructured":"Vanlangenakker N, vanden Berghe T, Bogaert P, Laukens B, Zobel K, Deshayes K, et al. cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1\/RIP3-dependent reactive oxygen species production. Cell Death Differ. 2011;18:656\u201365.","journal-title":"Cell Death Differ"},{"key":"3994_CR8","first-page":"37","volume":"403","author":"D Saleh","year":"2017","unstructured":"Saleh D, Degterev A. Emerging roles for RIPK1 and RIPK3 in pathogen-induced cell death and host immunity. Curr Top Microbiol Immunol. 2017;403:37\u201375.","journal-title":"Curr Top Microbiol Immunol"},{"key":"3994_CR9","doi-asserted-by":"crossref","unstructured":"Degterev A, Ofengeim D, Yuan J. Targeting RIPK1 for the treatment of human diseases. Proc Natl Acad Sci. 2019;116:9714\u20139722.","DOI":"10.1073\/pnas.1901179116"},{"key":"3994_CR10","doi-asserted-by":"crossref","unstructured":"Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ 2003;10:45\u201365.","DOI":"10.1038\/sj.cdd.4401189"},{"key":"3994_CR11","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.it.2016.06.002","volume":"37","author":"AT Ting","year":"2016","unstructured":"Ting AT, Bertrand MJM. More to life than NF-\u03baB in TNFR1 signaling. Trends Immunol. 2016;37:535\u201345.","journal-title":"Trends Immunol"},{"key":"3994_CR12","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.molmed.2017.11.002","volume":"24","author":"A Annibaldi","year":"2018","unstructured":"Annibaldi A, Meier P. Checkpoints in TNF-induced cell death: implications in inflammation and cancer. Trends Mol Med. 2018;24:49\u201365.","journal-title":"Trends Mol Med"},{"key":"3994_CR13","doi-asserted-by":"crossref","unstructured":"Delanghe T, Dondelinger Y, Bertrand MJM. RIPK1 kinase-dependent death: a symphony of phosphorylation events. Trends Cell Biol. 2020;30:189\u2013200.","DOI":"10.1016\/j.tcb.2019.12.009"},{"key":"3994_CR14","doi-asserted-by":"crossref","unstructured":"Newton K, Wickliffe KE, Dugger DL, Maltzman A, Roose-Girma M, Dohse M, et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. 2019;574:428\u201331.","DOI":"10.1038\/s41586-019-1548-x"},{"key":"3994_CR15","doi-asserted-by":"crossref","unstructured":"Zhang X, Dowling JP, Zhang J. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis. 2019;10:245.","DOI":"10.1038\/s41419-019-1490-8"},{"key":"3994_CR16","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s41586-019-1828-5","volume":"577","author":"N Lalaoui","year":"2020","unstructured":"Lalaoui N, Boyden SE, Oda H, Wood GM, Stone DL, Chau D, et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 2020;577:103\u20138.","journal-title":"Nature"},{"key":"3994_CR17","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1016\/j.cell.2009.05.037","volume":"137","author":"Y Cho","year":"2009","unstructured":"Cho Y, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009;137:1112\u201323.","journal-title":"Cell"},{"key":"3994_CR18","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.cell.2009.05.021","volume":"137","author":"S He","year":"2009","unstructured":"He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-\u03b1. Cell 2009;137:1100\u201311.","journal-title":"Cell"},{"key":"3994_CR19","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1126\/science.1172308","volume":"325","author":"DW Zhang","year":"2009","unstructured":"Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009;325:332\u20136.","journal-title":"Science"},{"key":"3994_CR20","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","volume":"148","author":"L Sun","year":"2012","unstructured":"Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012;148:213\u201327.","journal-title":"Cell"},{"key":"3994_CR21","doi-asserted-by":"publisher","first-page":"5322","DOI":"10.1073\/pnas.1200012109","volume":"109","author":"J Zhao","year":"2012","unstructured":"Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci USA. 2012;109:5322\u20137.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3994_CR22","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1038\/cdd.2013.94","volume":"20","author":"Y Dondelinger","year":"2013","unstructured":"Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E, et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1\/2 depletion or TAK1 kinase inhibition. Cell Death Differ. 2013;20:1381\u201392.","journal-title":"Cell Death Differ"},{"key":"3994_CR23","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.cell.2011.02.023","volume":"145","author":"S Biton","year":"2011","unstructured":"Biton S, Ashkenazi A. NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-\u03b1 feedforward signaling. Cell 2011;145:92\u2013103.","journal-title":"Cell"},{"key":"3994_CR24","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1038\/nchembio711","volume":"1","author":"A Degterev","year":"2005","unstructured":"Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112\u20139.","journal-title":"Nat Chem Biol"},{"key":"3994_CR25","doi-asserted-by":"publisher","first-page":"5317","DOI":"10.1016\/S0021-9258(18)42768-8","volume":"267","author":"K Schulze-Osthoff","year":"1992","unstructured":"Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem. 1992;267:5317\u201323.","journal-title":"J Biol Chem"},{"key":"3994_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14329","volume":"8","author":"Y Zhang","year":"2017","unstructured":"Zhang Y, Su SS, Zhao S, Yang Z, Zhong C-Q, Chen X, et al. RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome. Nat Commun 2017;8:14329.","journal-title":"Nat Commun"},{"key":"3994_CR27","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1038\/nature08206","volume":"460","author":"B Yazdanpanah","year":"2009","unstructured":"Yazdanpanah B, Wiegmann K, Tchikov V, Krut O, Pongratz C, Schramm M, et al. Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 2009;460:1159\u201363.","journal-title":"Nature"},{"key":"3994_CR28","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.molcel.2007.04.021","volume":"26","author":"YS Kim","year":"2007","unstructured":"Kim YS, Morgan MJ, Choksi S, Liu ZG. TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death. Mol Cell. 2007;26:675\u201387.","journal-title":"Mol Cell"},{"key":"3994_CR29","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1016\/j.celrep.2013.10.034","volume":"5","author":"SWG Tait","year":"2013","unstructured":"Tait SWG, Oberst A, Quarato G, Milasta S, Haller M, Wang R, et al. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis. Cell Rep. 2013;5:878\u201385.","journal-title":"Cell Rep"},{"key":"3994_CR30","doi-asserted-by":"crossref","unstructured":"Marshall KD, Baines CP. Necroptosis: is there a role for mitochondria? Front. Physiol. 2014;5:323.","DOI":"10.3389\/fphys.2014.00323"},{"key":"3994_CR31","doi-asserted-by":"publisher","first-page":"5796","DOI":"10.1038\/onc.2015.35","volume":"34","author":"B Schenk","year":"2015","unstructured":"Schenk B, Fulda S. Reactive oxygen species regulate Smac mimetic\/TNF\u03b1-induced necroptotic signaling and cell death. Oncogene 2015;34:5796\u2013806.","journal-title":"Oncogene"},{"key":"3994_CR32","doi-asserted-by":"publisher","first-page":"2215","DOI":"10.1128\/MCB.26.6.2215-2225.2006","volume":"26","author":"V Temkin","year":"2006","unstructured":"Temkin V, Huang Q, Liu H, Osada H, Pope RM. Inhibition of ADP\/ATP exchange in receptor-interacting protein-mediated necrosis. Mol Cell Biol. 2006;26:2215\u201325.","journal-title":"Mol Cell Biol"},{"key":"3994_CR33","doi-asserted-by":"crossref","unstructured":"Moquin D, Chan FKM The molecular regulation of programmed necrotic cell injury. Trends Biochem Sci. 2010;35:434\u201341.","DOI":"10.1016\/j.tibs.2010.03.001"},{"key":"3994_CR34","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/sj.cdd.4401746","volume":"13","author":"N Festjens","year":"2006","unstructured":"Festjens N, Kalai M, Smet J, Meeus A, van Coster R, Saelens X, et al. Butylated hydroxyanisole is more than a reactive oxygen species scavenger. Cell Death Differ. 2006;13:166\u20139.","journal-title":"Cell Death Differ"},{"key":"3994_CR35","doi-asserted-by":"crossref","unstructured":"Dondelinger Y, Delanghe T, Priem D, Wynosky-Dolfi MA, Sorobetea D, Rojas-Rivera D, et al. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat Commun. 2019;10:1729.","DOI":"10.1038\/s41467-019-09690-0"},{"key":"3994_CR36","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1128\/MCB.24.4.1464-1469.2004","volume":"24","author":"K Newton","year":"2004","unstructured":"Newton K, Sun X, Dixit VM. Kinase RIP3 is dispensable for normal NF-\u03baBs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and toll-like receptors 2 and 4. Mol Cell Biol. 2004;24:1464\u20139.","journal-title":"Mol Cell Biol"},{"key":"3994_CR37","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1038\/cdd.2012.90","volume":"19","author":"S Jouan-Lanhouet","year":"2012","unstructured":"Jouan-Lanhouet S, Arshad MI, Piquet-Pellorce C, Martin-Chouly C, le Moigne-Muller G, van Herreweghe F, et al. TRAIL induces necroptosis involving RIPK1\/RIPK3-dependent PARP-1 activation. Cell Death Differ. 2012;19:2003\u201314.","journal-title":"Cell Death Differ"},{"key":"3994_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0868-3","volume":"9","author":"H Guo","year":"2018","unstructured":"Guo H, Gilley RP, Fisher A, Lane R, Landsteiner VJ, Ragan KB, et al. Species-independent contribution of ZBP1\/DAI\/DLM-1-triggered necroptosis in host defense against HSV1. Cell Death Dis. 2018;9:816.","journal-title":"Cell Death Dis"},{"key":"3994_CR39","doi-asserted-by":"crossref","unstructured":"Yu X, He S. The interplay between human herpes simplex virus infection and the apoptosis and necroptosis cell death pathways. Virology. 2016;13:77.","DOI":"10.1186\/s12985-016-0528-0"},{"key":"3994_CR40","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.molcel.2014.10.021","volume":"56","author":"P Mandal","year":"2014","unstructured":"Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014;56:481\u201395.","journal-title":"Mol Cell"},{"key":"3994_CR41","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.molcel.2015.07.032","volume":"60","author":"Y Dondelinger","year":"2015","unstructured":"Dondelinger Y, Jouan-Lanhouet S, Divert T, Theatre E, Bertin J, Gough PJ, et al. NF-\u03baB-independent role of IKK\u03b1\/IKK\u03b2 in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol cell. 2015;60:63\u201376.","journal-title":"Mol cell"},{"key":"3994_CR42","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1038\/s41556-018-0229-6","volume":"20","author":"E Lafont","year":"2018","unstructured":"Lafont E, Draber P, Rieser E, Reichert M, Kupka S, de Miguel D, et al. TBK1 and IKK\u03b5 prevent TNF-induced cell death by RIPK1 phosphorylation. Nat Cell Biol. 2018;20:1389\u201399.","journal-title":"Nat Cell Biol"},{"key":"3994_CR43","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/j.cell.2018.07.041","volume":"174","author":"D Xu","year":"2018","unstructured":"Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell 2018;174:1477. e19","journal-title":"Cell"},{"key":"3994_CR44","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2008.03.036","volume":"133","author":"L Wang","year":"2008","unstructured":"Wang L, Du F, Wang X. TNF-\u03b1 induces two distinct caspase-8 activation pathways. Cell 2008;133:693\u2013703.","journal-title":"Cell"},{"key":"3994_CR45","doi-asserted-by":"crossref","unstructured":"Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016;73:2195\u2013209.","DOI":"10.1007\/s00018-016-2194-1"},{"key":"3994_CR46","doi-asserted-by":"crossref","unstructured":"Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273\u201385.","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"3994_CR47","doi-asserted-by":"crossref","unstructured":"Dondelinger Y, Delanghe T, Rojas-Rivera D, Priem D, Delvaeye T, Bruggeman I, et al. MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat. Cell Biol. 2017;19:1237\u201347.","DOI":"10.1038\/ncb3608"},{"key":"3994_CR48","doi-asserted-by":"crossref","unstructured":"Heger K, Wickliffe KE, Ndoja A, Zhang J, Murthy A, Dugger DL, et al. OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature. 2018;559:120\u201324.","DOI":"10.1038\/s41586-018-0256-2"},{"key":"3994_CR49","doi-asserted-by":"publisher","first-page":"252","DOI":"10.4103\/1673-5374.226394","volume":"13","author":"SA Cruz","year":"2018","unstructured":"Cruz SA, Qin Z, Stewart AFR, Chen HH. Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury. Neural Regener Res. 2018;13:252\u20136.","journal-title":"Neural Regener Res."},{"key":"3994_CR50","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1038\/cdd.2017.58","volume":"24","author":"D Rojas-Rivera","year":"2017","unstructured":"Rojas-Rivera D, Delvaeye T, Roelandt R, Nerinckx W, Augustyns K, Vandenabeele P, et al. When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157. Cell Death Differ. 2017;24:1100\u201310.","journal-title":"Cell Death Differ"},{"key":"3994_CR51","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/nchembio.83","volume":"4","author":"A Degterev","year":"2008","unstructured":"Degterev A, Hitomi J, Germscheid M, Ch\u2019en IL, Korkina O, Teng X, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4:313\u201321.","journal-title":"Nat Chem Biol"},{"key":"3994_CR52","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.str.2013.01.016","volume":"21","author":"T Xie","year":"2013","unstructured":"Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, et al. Structural basis of RIP1 inhibition by necrostatins. Structure 2013;21:493\u20139.","journal-title":"Structure"},{"key":"3994_CR53","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/j.immuni.2011.09.020","volume":"35","author":"L Duprez","year":"2011","unstructured":"Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, et al. RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 2011;35:908\u201318.","journal-title":"Immunity"},{"key":"3994_CR54","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1038\/cdd.2016.46","volume":"23","author":"K Newton","year":"2016","unstructured":"Newton K, Dugger DL, Maltzman A, Greve JM, Hedehus M, Martin-McNulty B, et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 2016;23:1565\u201376.","journal-title":"Cell Death Differ"},{"key":"3994_CR55","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/nrm2970","volume":"11","author":"P Vandenabeele","year":"2010","unstructured":"Vandenabeele P, Galluzzi L, vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010;11:700\u201314.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"3994_CR56","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/ni914","volume":"4","author":"A Cauwels","year":"2003","unstructured":"Cauwels A, Janssen B, Waeytens A, Cuvelier C, Brouckaert P. Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2. Nat Immunol. 2003;4:387\u201393.","journal-title":"Nat Immunol"},{"key":"3994_CR57","doi-asserted-by":"publisher","first-page":"5476","DOI":"10.4049\/jimmunol.1400499","volume":"192","author":"SB Berger","year":"2014","unstructured":"Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol. 2014;192:5476\u201380.","journal-title":"J Immunol"},{"key":"3994_CR58","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/s41418-019-0347-0","volume":"27","author":"S Patel","year":"2020","unstructured":"Patel S, Webster JD, Varfolomeev E, Kwon YC, Cheng JH, Zhang J, et al. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ. 2020;27:161\u201375.","journal-title":"Cell Death Differ"},{"key":"3994_CR59","doi-asserted-by":"crossref","unstructured":"Vlantis K, Wullaert A, Polykratis A, Kondylis V, Dannappel M, Schwarzer R, et al. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-\u03baB-dependent and -independent functions. Immunity. 2016;44:553\u201367.","DOI":"10.1016\/j.immuni.2016.02.020"},{"key":"3994_CR60","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.ccr.2006.12.016","volume":"11","author":"T Luedde","year":"2007","unstructured":"Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, de Vos R, et al. Deletion of NEMO\/IKK\u03b3 in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2007;11:119\u201332.","journal-title":"Cancer Cell"},{"key":"3994_CR61","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1016\/j.ccell.2015.10.001","volume":"28","author":"V Kondylis","year":"2015","unstructured":"Kondylis V, Polykratis A, Ehlken H, Ochoa-Callejero L, Straub BK, Krishna-Subramanian S, et al. NEMO prevents steatohepatitis and hepatocellular carcinoma by inhibiting RIPK1 kinase activity-mediated hepatocyte apoptosis. Cancer Cell. 2015;28:582\u201398.","journal-title":"Cancer Cell"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03994-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03994-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03994-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T09:05:58Z","timestamp":1669971958000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03994-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,14]]},"references-count":61,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["3994"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-03994-0","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,14]]},"assertion":[{"value":"31 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 July 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study did not make use of human participants and therefore did not require consent. All experiments on mice were conducted according to institutional, national, and European animal regulations. Animal protocols were approved by the ethical committee of Ghent University (EC2017\u2013071, EC2017\u2013079).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"699"}}