{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:44:59Z","timestamp":1792565099028,"version":"4.5.0"},"reference-count":82,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Cellular stress signaling conveys vital messages to the cell's machinery to respond dynamically to internal and external environmental cues. One prevailing hypothesis for such signaling is to bring about crucial downstream functional changes in the cell's ability to withstand intra\u2010 and extra\u2010cellular stress, as exemplified by the NRF2\u2010ARE pathway. Reactive electrophilic metabolites (REMs)\u2014exemplified by the lipid\u2010derived electrophile, 4\u2010hydroxynonenal\u2014are often generated from membrane lipids or respiratory metabolites in inflammatory and stress signaling contexts. REMs harbor an innate ability to irreversibly bind protein\u2010cysteines and form DNA and RNA adducts. Our work has led us to propose a new hypothesis regarding the role of\n                    <jats:italic>locale\u2010specific<\/jats:italic>\n                    REM build\u2010up in stress signaling; whereby, they can label both the majority stable protein residents in a given locale and the minority guests transiently existing within a subcellular compartment at a kinetically significant rate to trigger a \u2018gain of function\u2019 signaling cascade. Much like the NRF2 signaling pathway, such downstream signaling messages could assist the cell's ability to survive against microenvironment\u2010specific stress and adapt on demand. As REMs accumulate in several disease\u2010specific cells, especially age\u2010related disorders such as cancer and neurodegeneration, understanding the functional signal propagation mechanisms shaped by specific REMs engaging with specific biomolecular targets will prove vital for future therapeutic interventions with enhanced precision and context.\n                  <\/jats:p>","DOI":"10.1111\/febs.70754","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:04:32Z","timestamp":1792562672000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brief encounters and lasting impressions\u2014How target protein half\u2010life affects reactive metabolite signaling"],"prefix":"10.1111","author":[{"given":"Marcus J. C.","family":"Long","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Oxford  UK"},{"name":"Department of Pharmacology University of Oxford  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna","family":"Birkby","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Oxford  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1256-4159","authenticated-orcid":false,"given":"Yimon","family":"Aye","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Oxford  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"e_1_2_21_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(91)90192-6"},{"key":"e_1_2_21_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00698"},{"key":"e_1_2_21_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr200131e"},{"key":"e_1_2_21_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R700051200"},{"key":"e_1_2_21_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ht7020012"},{"key":"e_1_2_21_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-024-01282-4"},{"key":"e_1_2_21_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25466-x"},{"key":"e_1_2_21_9_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S236926"},{"key":"e_1_2_21_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.1c00980"},{"key":"e_1_2_21_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmd.2024.100027"},{"key":"e_1_2_21_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-025-03162-7"},{"key":"e_1_2_21_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2284"},{"key":"e_1_2_21_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.9b00893"},{"key":"e_1_2_21_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00044"},{"key":"e_1_2_21_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi2002289"},{"key":"e_1_2_21_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2008.08.006"},{"key":"e_1_2_21_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812149106"},{"key":"e_1_2_21_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2024.101482"},{"key":"e_1_2_21_20_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1999.1277"},{"key":"e_1_2_21_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.10.014"},{"key":"e_1_2_21_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10050701"},{"key":"e_1_2_21_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10101429"},{"key":"e_1_2_21_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-025-04276-w"},{"key":"e_1_2_21_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2006.09.012"},{"key":"e_1_2_21_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1544"},{"key":"e_1_2_21_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-026-01743-x"},{"key":"e_1_2_21_28_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100726RR"},{"key":"e_1_2_21_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.138"},{"key":"e_1_2_21_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2014.08.001"},{"key":"e_1_2_21_31_1","doi-asserted-by":"publisher","DOI":"10.3109\/10715762.2010.498477"},{"key":"e_1_2_21_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/95.12.803"},{"key":"e_1_2_21_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.03.004"},{"key":"e_1_2_21_34_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.117.110742"},{"key":"e_1_2_21_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010903"},{"key":"e_1_2_21_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.molbev.a026406"},{"key":"e_1_2_21_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-025-02135-4"},{"key":"e_1_2_21_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja5084249"},{"key":"e_1_2_21_39_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.10.21"},{"key":"e_1_2_21_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313733111"},{"key":"e_1_2_21_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15121699"},{"key":"e_1_2_21_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2013.09.003"},{"key":"e_1_2_21_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2019.02.039"},{"key":"e_1_2_21_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2018.09.014"},{"key":"e_1_2_21_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-023-00809-8"},{"key":"e_1_2_21_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.114"},{"key":"e_1_2_21_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2120687119"},{"key":"e_1_2_21_48_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.83373"},{"key":"e_1_2_21_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.7b00925"},{"key":"e_1_2_21_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.990874"},{"key":"e_1_2_21_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11030-025-11132-7"},{"key":"e_1_2_21_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja5132648"},{"key":"e_1_2_21_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105526"},{"key":"e_1_2_21_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M111.011429"},{"key":"e_1_2_21_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00287-9"},{"key":"e_1_2_21_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2011.09.010"},{"key":"e_1_2_21_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2009.05.008"},{"key":"e_1_2_21_58_1","first-page":"69","article-title":"Decision making by p53: life versus death","volume":"2","author":"Jiang L","year":"2010","journal-title":"Mol Cell Pharmacol"},{"key":"e_1_2_21_59_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.7.2423-2435.2000"},{"key":"e_1_2_21_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdf567"},{"key":"e_1_2_21_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-35795-8"},{"key":"e_1_2_21_62_1","doi-asserted-by":"publisher","DOI":"10.1039\/D5CB00230C"},{"key":"e_1_2_21_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.211"},{"key":"e_1_2_21_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0217-y"},{"key":"e_1_2_21_65_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.7b00556"},{"key":"e_1_2_21_66_1","first-page":"3867","article-title":"A potent specific pure antiestrogen with clinical potential","volume":"51","author":"Wakeling AE","year":"1991","journal-title":"Cancer Res"},{"key":"e_1_2_21_67_1","doi-asserted-by":"publisher","DOI":"10.21037\/tcr-20-2166"},{"key":"e_1_2_21_68_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1177319"},{"key":"e_1_2_21_69_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-022123-104147"},{"key":"e_1_2_21_70_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.141230798"},{"key":"e_1_2_21_71_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02371"},{"key":"e_1_2_21_72_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43556-022-00112-0"},{"key":"e_1_2_21_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2020.07.013"},{"key":"e_1_2_21_74_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.8b01094"},{"key":"e_1_2_21_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b13907"},{"key":"e_1_2_21_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0279-5"},{"key":"e_1_2_21_77_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.472092"},{"key":"e_1_2_21_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3173"},{"key":"e_1_2_21_79_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11030\u2010025\u201011273\u20109"},{"key":"e_1_2_21_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.09.010"},{"key":"e_1_2_21_81_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.73130.1"},{"key":"e_1_2_21_82_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2020771"},{"key":"e_1_2_21_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3235"}],"container-title":["The FEBS Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70754","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/febs.70754","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/febs.70754","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T06:04:33Z","timestamp":1792562673000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1111\/febs.70754"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,20]]},"references-count":82,"alternative-id":["10.1111\/febs.70754"],"URL":"https:\/\/doi.org\/10.1111\/febs.70754","archive":["Portico"],"relation":{},"ISSN":["1742-464X","1742-4658"],"issn-type":[{"value":"1742-464X","type":"print"},{"value":"1742-4658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,20]]},"assertion":[{"value":"2026-04-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"febs.70754"}}