{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T17:43:56Z","timestamp":1792950236457,"version":"4.5.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R35CA197583"],"award-info":[{"award-number":["R35CA197583"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R50CA211399"],"award-info":[{"award-number":["R50CA211399"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R35CA231991"],"award-info":[{"award-number":["R35CA231991"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Chem Biol"],"DOI":"10.1038\/s41589-026-02297-9","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:02:53Z","timestamp":1787907773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2567-8552","authenticated-orcid":false,"given":"Peiwen","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9708-5287","authenticated-orcid":false,"given":"Bruno","family":"Melillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"McHenry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Camara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3508-2638","authenticated-orcid":false,"given":"Evert","family":"Njomen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Godes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Pazyra-Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Rose","family":"Branch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Tesar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9850-8432","authenticated-orcid":false,"given":"Rosalind A.","family":"Segal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee L.","family":"Rubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3154-4775","authenticated-orcid":false,"given":"Michael D.","family":"Cameron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory H.","family":"Bird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6133-5689","authenticated-orcid":false,"given":"Thomas E.","family":"Wales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7626-0034","authenticated-orcid":false,"given":"Steven P.","family":"Gygi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5330-3492","authenticated-orcid":false,"given":"Benjamin F.","family":"Cravatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-2334","authenticated-orcid":false,"given":"Loren D.","family":"Walensky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"2297_CR1","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/S0092-8674(00)00167-7","volume":"103","author":"M Suzuki","year":"2000","unstructured":"Suzuki, M., Youle, R. J. & Tjandra, N. Structure of BAX: coregulation of dimer formation and intracellular localization. Cell 103, 645\u2013654 (2000).","journal-title":"Cell"},{"key":"2297_CR2","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.tibs.2011.08.009","volume":"36","author":"LD Walensky","year":"2011","unstructured":"Walensky, L. D. & Gavathiotis, E. BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore. Trends Biochem. Sci 36, 642\u2013652 (2011).","journal-title":"Trends Biochem. Sci"},{"key":"2297_CR3","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/s41589-019-0306-6","volume":"15","author":"LD Walensky","year":"2019","unstructured":"Walensky, L. D. Targeting BAX to drug death directly. Nat. Chem. Biol. 15, 657\u2013665 (2019).","journal-title":"Nat. Chem. Biol."},{"key":"2297_CR4","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1152\/physrev.00022.2018","volume":"99","author":"DP Del Re","year":"2019","unstructured":"Del Re, D. P., Amgalan, D., Linkermann, A., Liu, Q. & Kitsis, R. N. Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol. Rev. 99, 1765\u20131817 (2019).","journal-title":"Physiol. Rev."},{"key":"2297_CR5","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1097\/00004647-200104000-00001","volume":"21","author":"G Cao","year":"2001","unstructured":"Cao, G. et al. Intracellular BAX translocation after transient cerebral ischemia: implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J. Cereb. Blood Flow Metab. 21, 321\u2013333 (2001).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2297_CR6","doi-asserted-by":"publisher","first-page":"e309","DOI":"10.1038\/cddis.2012.43","volume":"3","author":"W Kudo","year":"2012","unstructured":"Kudo, W. et al. Inhibition of BAX protects neuronal cells from oligomeric A\u03b2 neurotoxicity. Cell Death Dis. 3, e309 (2012).","journal-title":"Cell Death Dis."},{"key":"2297_CR7","doi-asserted-by":"publisher","first-page":"8774","DOI":"10.1523\/JNEUROSCI.2315-06.2006","volume":"26","author":"TW Gould","year":"2006","unstructured":"Gould, T. W. et al. Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J. Neurosci. 26, 8774\u20138786 (2006).","journal-title":"J. Neurosci."},{"key":"2297_CR8","doi-asserted-by":"publisher","first-page":"H2351","DOI":"10.1152\/ajpheart.00783.2002","volume":"284","author":"E Hochhauser","year":"2003","unstructured":"Hochhauser, E. et al. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am. J. Physiol. Heart Circ. Physiol. 284, H2351\u2013H2359 (2003).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2297_CR9","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1523\/JNEUROSCI.2453-14.2015","volume":"35","author":"B D\u2019Orsi","year":"2015","unstructured":"D\u2019Orsi, B. et al. BAX regulates neuronal Ca2+ homeostasis. J. Neurosci. 35, 1706\u20131722 (2015).","journal-title":"J. Neurosci."},{"key":"2297_CR10","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1038\/nature07396","volume":"455","author":"E Gavathiotis","year":"2008","unstructured":"Gavathiotis, E. et al. BAX activation is initiated at a novel interaction site. Nature 455, 1076\u20131081 (2008).","journal-title":"Nature"},{"key":"2297_CR11","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1016\/j.cell.2012.01.038","volume":"148","author":"JE Chipuk","year":"2012","unstructured":"Chipuk, J. E. et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148, 988\u20131000 (2012).","journal-title":"Cell"},{"key":"2297_CR12","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.molcel.2015.01.014","volume":"57","author":"LA Barclay","year":"2015","unstructured":"Barclay, L. A. et al. Inhibition of pro-apoptotic BAX by a noncanonical interaction mechanism. Mol. Cell 57, 873\u2013886 (2015).","journal-title":"Mol. Cell"},{"key":"2297_CR13","doi-asserted-by":"publisher","first-page":"7988","DOI":"10.1073\/pnas.0401897101","volume":"101","author":"D Arnoult","year":"2004","unstructured":"Arnoult, D. et al. Cytomegalovirus cell death suppressor vMIA blocks BAX- but not BAK-mediated apoptosis by binding and sequestering BAX at mitochondria. Proc. Natl. Acad. Sci. USA 101, 7988\u20137993 (2004).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2297_CR14","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/s41589-018-0223-0","volume":"15","author":"TP Garner","year":"2019","unstructured":"Garner, T. P. et al. Small-molecule allosteric inhibitors of BAX. Nat. Chem. Biol. 15, 322\u2013330 (2019).","journal-title":"Nat. Chem. Biol."},{"key":"2297_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21224-1","volume":"12","author":"AZ Spitz","year":"2021","unstructured":"Spitz, A. Z., Zacharioudakis, E., Reyna, D. E., Garner, T. P. & Gavathiotis, E. Eltrombopag directly inhibits BAX and prevents cell death. Nat. Commun. 12, 1134 (2021).","journal-title":"Nat. Commun."},{"key":"2297_CR16","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.chembiol.2017.03.011","volume":"24","author":"X Niu","year":"2017","unstructured":"Niu, X. et al. A small-molecule inhibitor of BAX and BAK oligomerization prevents genotoxic cell death and promotes neuroprotection. Cell Chem. Biol. 24, 493\u2013506 (2017).","journal-title":"Cell Chem. Biol."},{"key":"2297_CR17","doi-asserted-by":"publisher","first-page":"3229","DOI":"10.1016\/j.celrep.2020.02.057","volume":"30","author":"DT Cohen","year":"2020","unstructured":"Cohen, D. T., Wales, T. E., McHenry, M. W., Engen, J. R. & Walensky, L. D. Site-dependent cysteine lipidation potentiates the activation of proapoptotic BAX. Cell Rep. 30, 3229\u20133239 (2020).","journal-title":"Cell Rep."},{"key":"2297_CR18","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/s41589-023-01537-6","volume":"20","author":"MW McHenry","year":"2024","unstructured":"McHenry, M. W. et al. Covalent inhibition of pro-apoptotic BAX. Nat. Chem. Biol. 20, 1022\u20131032 (2024).","journal-title":"Nat. Chem. Biol."},{"key":"2297_CR19","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1038\/s41573-022-00542-z","volume":"21","author":"L Boike","year":"2022","unstructured":"Boike, L., Henning, N. J. & Nomura, D. K. Advances in covalent drug discovery. Nat. Rev. Drug Discov. 21, 881\u2013898 (2022).","journal-title":"Nat. Rev. Drug Discov."},{"key":"2297_CR20","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1021\/acs.accounts.1c00065","volume":"54","author":"JN Spradlin","year":"2021","unstructured":"Spradlin, J. N., Zhang, E. & Nomura, D. K. Reimagining druggability using chemoproteomic platforms. Acc. Chem. Res. 54, 1801\u20131813 (2021).","journal-title":"Acc. Chem. Res."},{"key":"2297_CR21","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1016\/j.chembiol.2024.08.006","volume":"31","author":"MJ Niphakis","year":"2024","unstructured":"Niphakis, M. J. & Cravatt, B. F. Ligand discovery by activity-based protein profiling. Cell Chem. Biol. 31, 1636\u20131651 (2024).","journal-title":"Cell Chem. Biol."},{"key":"2297_CR22","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1038\/nature09472","volume":"468","author":"E Weerapana","year":"2010","unstructured":"Weerapana, E. et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468, 790\u2013795 (2010).","journal-title":"Nature"},{"key":"2297_CR23","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1038\/nature18002","volume":"534","author":"KM Backus","year":"2016","unstructured":"Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570\u2013574 (2016).","journal-title":"Nature"},{"key":"2297_CR24","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1038\/s41557-024-01601-1","volume":"16","author":"E Njomen","year":"2024","unstructured":"Njomen, E. et al. Multi-tiered chemical proteomic maps of tryptoline acrylamide-protein interactions in cancer cells. Nat. Chem. 16, 1592\u20131604 (2024).","journal-title":"Nat. Chem."},{"key":"2297_CR25","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1016\/j.cell.2020.07.001","volume":"182","author":"EV Vinogradova","year":"2020","unstructured":"Vinogradova, E. V. et al. An activity-guided map of electrophile\u2013cysteine interactions in primary human T cells. Cell 182, 1009\u20131026 (2020).","journal-title":"Cell"},{"key":"2297_CR26","doi-asserted-by":"publisher","first-page":"11272","DOI":"10.1073\/pnas.0504783102","volume":"102","author":"O Takeuchi","year":"2005","unstructured":"Takeuchi, O. et al. Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease. Proc. Natl Acad. Sci. USA 102, 11272\u201311277 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2297_CR27","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.molcel.2010.10.019","volume":"40","author":"E Gavathiotis","year":"2010","unstructured":"Gavathiotis, E., Reyna, D. E., Davis, M. L., Bird, G. H. & Walensky, L. D. BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol. Cell 40, 481\u2013492 (2010).","journal-title":"Mol. Cell"},{"key":"2297_CR28","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.molcel.2020.05.029","volume":"79","author":"ZJ Hauseman","year":"2020","unstructured":"Hauseman, Z. J. et al. Homogeneous oligomers of pro-apoptotic BAX reveal structural determinants of mitochondrial membrane permeabilization. Mol. Cell 79, 68\u201383 (2020).","journal-title":"Mol. Cell"},{"key":"2297_CR29","doi-asserted-by":"publisher","first-page":"7870","DOI":"10.1021\/ac901154s","volume":"81","author":"JR Engen","year":"2009","unstructured":"Engen, J. R. Analysis of protein conformation and dynamics by hydrogen\/deuterium exchange MS. Anal. Chem. 81, 7870\u20137875 (2009).","journal-title":"Anal. Chem."},{"key":"2297_CR30","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1038\/nchembio.2433","volume":"13","author":"JR Pritz","year":"2017","unstructured":"Pritz, J. R. et al. Allosteric sensitization of proapoptotic BAX. Nat. Chem. Biol. 13, 961\u2013967 (2017).","journal-title":"Nat. Chem. Biol."},{"key":"2297_CR31","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1021\/cr040109f","volume":"106","author":"PK Chattaraj","year":"2006","unstructured":"Chattaraj, P. K., Sarkar, U. & Roy, D. R. Electrophilicity index. Chem. Rev. 106, 2065\u20132091 (2006).","journal-title":"Chem. Rev."},{"key":"2297_CR32","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2023.1327361","volume":"17","author":"ME Watts","year":"2023","unstructured":"Watts, M. E. et al. Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets. Front. Cell Neurosci. 17, 1327361 (2023).","journal-title":"Front. Cell Neurosci."},{"key":"2297_CR33","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.neuron.2013.12.018","volume":"81","author":"NH Alami","year":"2014","unstructured":"Alami, N. H. et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81, 536\u2013543 (2014).","journal-title":"Neuron"},{"key":"2297_CR34","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1523\/JNEUROSCI.4988-09.2010","volume":"30","author":"SJ Barmada","year":"2010","unstructured":"Barmada, S. J. et al. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J. Neurosci. 30, 639\u2013649 (2010).","journal-title":"J. Neurosci."},{"key":"2297_CR35","doi-asserted-by":"publisher","first-page":"6715","DOI":"10.1021\/ac501849n","volume":"86","author":"MA Sowole","year":"2014","unstructured":"Sowole, M. A. & Konermann, L. Effects of protein\u2013ligand interactions on hydrogen\/deuterium exchange kinetics: canonical and noncanonical scenarios. Anal. Chem. 86, 6715\u20136722 (2014).","journal-title":"Anal. Chem."},{"key":"2297_CR36","doi-asserted-by":"publisher","first-page":"6364","DOI":"10.1523\/JNEUROSCI.15-10-06364.1995","volume":"15","author":"S Krajewski","year":"1995","unstructured":"Krajewski, S. et al. Upregulation of BAX protein levels in neurons following cerebral ischemia. J. Neurosci. 15, 6364\u20136376 (1995).","journal-title":"J. Neurosci."},{"key":"2297_CR37","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1089\/neu.2007.0441","volume":"25","author":"R Tehranian","year":"2008","unstructured":"Tehranian, R. et al. Disruption of BAX protein prevents neuronal cell death but produces cognitive impairment in mice following traumatic brain injury. J. Neurotrauma 25, 755\u2013767 (2008).","journal-title":"J. Neurotrauma"},{"key":"2297_CR38","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1007\/BF03401871","volume":"7","author":"ME Gibson","year":"2001","unstructured":"Gibson, M. E. et al. BAX contributes to apoptotic-like death following neonatal hypoxia\u2013ischemia: evidence for distinct apoptosis pathways. Mol. Med. 7, 644\u2013655 (2001).","journal-title":"Mol. Med."},{"key":"2297_CR39","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1038\/ki.2013.68","volume":"84","author":"Q Wei","year":"2013","unstructured":"Wei, Q., Dong, G., Chen, J. K., Ramesh, G. & Dong, Z. BAX and BAK have critical roles in ischemic acute kidney injury in global and proximal tubule-specific knockout mouse models. Kidney Int. 84, 138\u2013148 (2013).","journal-title":"Kidney Int."},{"key":"2297_CR40","doi-asserted-by":"publisher","first-page":"2837","DOI":"10.1073\/pnas.051633998","volume":"98","author":"M Vila","year":"2001","unstructured":"Vila, M. et al. Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson\u2019s disease. Proc. Natl Acad. Sci. USA 98, 2837\u20132842 (2001).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2297_CR41","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.neulet.2004.01.076","volume":"359","author":"N Lev","year":"2004","unstructured":"Lev, N., Barhum, Y., Melamed, E. & Offen, D. Bax-ablation attenuates experimental autoimmune encephalomyelitis in mice. Neurosci. Lett. 359, 139\u2013142 (2004).","journal-title":"Neurosci. Lett."},{"key":"2297_CR42","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1073\/pnas.0406173102","volume":"102","author":"R Chiesa","year":"2005","unstructured":"Chiesa, R. et al. Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease. Proc. Natl Acad. Sci. USA 102, 238\u2013243 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2297_CR43","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/s43018-020-0039-1","volume":"1","author":"D Amgalan","year":"2020","unstructured":"Amgalan, D. et al. A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy. Nat. Cancer 1, 315\u2013328 (2020).","journal-title":"Nat. Cancer"},{"key":"2297_CR44","doi-asserted-by":"publisher","first-page":"e331","DOI":"10.1161\/STROKEAHA.108.531632","volume":"40","author":"BR Broughton","year":"2009","unstructured":"Broughton, B. R., Reutens, D. C. & Sobey, C. G. Apoptotic mechanisms after cerebral ischemia. Stroke 40, e331\u2013e339 (2009).","journal-title":"Stroke"},{"key":"2297_CR45","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1159\/000091699","volume":"21","author":"I Ferrer","year":"2006","unstructured":"Ferrer, I. Apoptosis: future targets for neuroprotective strategies. Cerebrovasc. Dis. 21, 9\u201320 (2006).","journal-title":"Cerebrovasc. Dis."},{"key":"2297_CR46","doi-asserted-by":"publisher","first-page":"3162","DOI":"10.1021\/ct200328p","volume":"7","author":"O Guvench","year":"2011","unstructured":"Guvench, O. et al. CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate\u2013protein modeling. J. Chem. Theory Comput. 7, 3162\u20133180 (2011).","journal-title":"J. Chem. Theory Comput."},{"key":"2297_CR47","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1002\/jcc.23354","volume":"34","author":"J Huang","year":"2013","unstructured":"Huang, J. & MacKerell, A. D. Jr. CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J. Comput. Chem. 34, 2135\u20132145 (2013).","journal-title":"J. Comput. Chem."},{"key":"2297_CR48","doi-asserted-by":"publisher","first-page":"3586","DOI":"10.1021\/jp973084f","volume":"102","author":"AD MacKerell","year":"1998","unstructured":"MacKerell, A. D. et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586\u20133616 (1998).","journal-title":"J. Phys. Chem. B"},{"key":"2297_CR49","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1002\/jcc.20065","volume":"25","author":"AD Mackerell Jr.","year":"2004","unstructured":"Mackerell, A. D. Jr., Feig, M. & Brooks, C. L. III. Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J. Comput. Chem. 25, 1400\u20131415 (2004).","journal-title":"J. Comput. Chem."},{"key":"2297_CR50","doi-asserted-by":"publisher","DOI":"10.1063\/5.0014475","volume":"153","author":"JC Phillips","year":"2020","unstructured":"Phillips, J. C. et al. Scalable molecular dynamics on CPU and GPU architectures with NAMD. J. Chem. Phys. 153, 044130 (2020).","journal-title":"J. Chem. Phys."},{"key":"2297_CR51","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","volume":"23","author":"J-P Ryckaert","year":"1977","unstructured":"Ryckaert, J.-P., Ciccotti, G. & Berendsen, H.J.C. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23, 327\u2013341 (1977).","journal-title":"J. Comput. Phys."},{"key":"2297_CR52","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","volume":"17","author":"C Lu","year":"2021","unstructured":"Lu, C. et al. OPLS4: improving force field accuracy on challenging regimes of chemical space. J. Chem. Theory Comput. 17, 4291\u20134300 (2021).","journal-title":"J. Chem. Theory Comput."},{"key":"2297_CR53","doi-asserted-by":"publisher","first-page":"5648","DOI":"10.1063\/1.464913","volume":"98","author":"AD Becke","year":"1998","unstructured":"Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648\u20135652 (1998).","journal-title":"J. Chem. Phys."},{"key":"2297_CR54","doi-asserted-by":"publisher","first-page":"11623","DOI":"10.1021\/j100096a001","volume":"98","author":"PJ Stephens","year":"1994","unstructured":"Stephens, P. J., Devlin, F. J., Chabalowski, C. F. & Frisch, M. J. Calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J. Phys. Chem. 98, 11623 (1994).","journal-title":"J. Phys. Chem."},{"key":"2297_CR55","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.1002\/qua.24481","volume":"113","author":"AD Bochevarov","year":"2013","unstructured":"Bochevarov, A. D. et al. Jaguar: a high-performance quantum chemistry software program with strengths in life and materials sciences. Int. J. Quantum Chem. 113, 2110\u20132142 (2013).","journal-title":"Int. J. Quantum Chem."},{"key":"2297_CR56","doi-asserted-by":"publisher","first-page":"3297","DOI":"10.1039\/b508541a","volume":"7","author":"F Weigend","year":"2005","unstructured":"Weigend, F. & Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn. Phys. Chem. Chem. Phys. 7, 3297\u20133305 (2005).","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2297_CR57","doi-asserted-by":"publisher","DOI":"10.1063\/1.3382344","volume":"132","author":"S Grimme","year":"2010","unstructured":"Grimme, S., Antony, J., Ehrlich, S. & Kreig, H. A consistent and accurate ab initio parametrization of density functio nal dispersion correction energy (DFT-D) for the 94 elements H\u2013Pu. J. Chem. Phys. 132, 154104 (2010).","journal-title":"J. Chem. Phys."},{"key":"2297_CR58","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1002\/jcc.10189","volume":"24","author":"M Cossi","year":"2003","unstructured":"Cossi, M., Rega, N., Scalmani, G. & Barone, V. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J. Comput. Chem. 24, 669\u2013681 (2003).","journal-title":"J. Comput. Chem."},{"key":"2297_CR59","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.70019","volume":"15","author":"F Neese","year":"2025","unstructured":"Neese, F. Software update: the ORCA program system\u2014version 6.0. WIRES Comput. Mol. Sci. 15, e70019 (2025).","journal-title":"WIRES Comput. Mol. Sci."},{"key":"2297_CR60","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41592-020-0781-4","volume":"17","author":"J Li","year":"2020","unstructured":"Li, J. et al. TMTpro reagents: a set of isobaric labeling mass tags enables simultaneous proteome-wide measurements across 16 samples. Nat. Methods 17, 399\u2013404 (2020).","journal-title":"Nat. Methods"},{"key":"2297_CR61","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36269-7","volume":"14","author":"Q Yu","year":"2023","unstructured":"Yu, Q. et al. Sample multiplexing-based targeted pathway proteomics with real-time analytics reveals the impact of genetic variation on protein expression. Nat. Commun. 14, 555 (2023).","journal-title":"Nat. Commun."},{"key":"2297_CR62","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.1021\/acs.jproteome.9b00860","volume":"19","author":"DK Schweppe","year":"2020","unstructured":"Schweppe, D. K. et al. Full-featured, real-time database searching platform enables fast and accurate multiplexed quantitative proteomics. J. Proteome Res. 19, 2026\u20132034 (2020).","journal-title":"J. Proteome Res."},{"key":"2297_CR63","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1002\/pmic.201200439","volume":"13","author":"JK Eng","year":"2013","unstructured":"Eng, J. K., Jahan, T. A. & Hoopmann, M. R. Comet: an open-source MS\/MS sequence database search tool. Proteomics 13, 22\u201324 (2013).","journal-title":"Proteomics"},{"key":"2297_CR64","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nmeth1019","volume":"4","author":"JE Elias","year":"2007","unstructured":"Elias, J. E. & Gygi, S. P. Target\u2013decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat. Methods 4, 207\u2013214 (2007).","journal-title":"Nat. Methods"},{"key":"2297_CR65","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1016\/j.cell.2010.12.001","volume":"143","author":"EL Huttlin","year":"2010","unstructured":"Huttlin, E. L. et al. A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143, 1174\u20131189 (2010).","journal-title":"Cell"},{"key":"2297_CR66","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1074\/mcp.M114.046995","volume":"14","author":"MM Savitski","year":"2015","unstructured":"Savitski, M. M., Wilhelm, M., Hahne, H., Kuster, B. & Bantscheff, M. A scalable approach for protein false discovery rate estimation in large proteomic data sets. Mol. Cell. Proteomics 14, 2394\u20132404 (2015).","journal-title":"Mol. Cell. Proteomics"},{"key":"2297_CR67","doi-asserted-by":"publisher","first-page":"2226","DOI":"10.1021\/acs.jproteome.8b00217","volume":"17","author":"J Navarrete-Perea","year":"2018","unstructured":"Navarrete-Perea, J., Yu, Q., Gygi, S. P. & Paulo, J. A. Streamlined tandem mass tag (SL-TMT) protocol: an efficient strategy for quantitative (phospho)proteome profiling using tandem mass tag-synchronous precursor selection-MS3. J. Proteome Res. 17, 2226\u20132236 (2018).","journal-title":"J. Proteome Res."},{"key":"2297_CR68","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128 (2013).","journal-title":"BMC Bioinformatics"},{"key":"2297_CR69","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nbt.3049","volume":"33","author":"Y Maury","year":"2015","unstructured":"Maury, Y. et al. Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nat. Biotechnol. 33, 89\u201396 (2015).","journal-title":"Nat. Biotechnol."},{"key":"2297_CR70","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1016\/j.neuron.2023.02.019","volume":"111","author":"DV Neel","year":"2023","unstructured":"Neel, D. V. et al. Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration. Neuron 111, 1222\u20131240 (2023).","journal-title":"Neuron"}],"container-title":["Nature Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41589-026-02297-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41589-026-02297-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41589-026-02297-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:02:55Z","timestamp":1787907775000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41589-026-02297-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":70,"alternative-id":["2297"],"URL":"https:\/\/doi.org\/10.1038\/s41589-026-02297-9","relation":{},"ISSN":["1552-4450","1552-4469"],"issn-type":[{"value":"1552-4450","type":"print"},{"value":"1552-4469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]},"assertion":[{"value":"25 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors have filed a patent application related to this work.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}