{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:26:08Z","timestamp":1789413968003,"version":"build-2803163510"},"reference-count":115,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["19-00121S and 20-00058S"],"award-info":[{"award-number":["19-00121S and 20-00058S"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["1160120"],"award-info":[{"award-number":["1160120"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004240","name":"Czech Academy of Sciences","doi-asserted-by":"publisher","award":["RVO:67985823"],"award-info":[{"award-number":["RVO:67985823"]}],"id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Apoptosis signal-regulating kinase (ASK) 1, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, modulates diverse responses to oxidative and endoplasmic reticulum (ER) stress and calcium influx. As a crucial cellular stress sensor, ASK1 activates c-Jun N-terminal kinases (JNKs) and p38 MAPKs. Their excessive and sustained activation leads to cell death, inflammation and fibrosis in various tissues and is implicated in the development of many neurological disorders, such as Alzheimer\u2019s, Parkinson\u2019s and Huntington disease and amyotrophic lateral sclerosis, in addition to cardiovascular diseases, diabetes and cancer. However, currently available inhibitors of JNK and p38 kinases either lack efficacy or have undesirable side effects. Therefore, targeted inhibition of their upstream activator, ASK1, stands out as a promising therapeutic strategy for treating such severe pathological conditions. This review summarizes recent structural findings on ASK1 regulation and its role in various diseases, highlighting prospects for ASK1 inhibition in the treatment of these pathologies.<\/jats:p>","DOI":"10.3390\/ijms222413395","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T01:20:41Z","timestamp":1639444841000},"page":"13395","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4887-0323","authenticated-orcid":false,"given":"Veronika","family":"Obsilova","sequence":"first","affiliation":[{"name":"Department of Structural Biology of Signaling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, 25250 Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Honzejkova","sequence":"additional","affiliation":[{"name":"Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, 12843 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4602-1272","authenticated-orcid":false,"given":"Tomas","family":"Obsil","sequence":"additional","affiliation":[{"name":"Department of Structural Biology of Signaling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, 25250 Vestec, Czech Republic"},{"name":"Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, 12843 Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1126\/science.275.5296.90","article-title":"Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK\/JNK and p38 Signaling Pathways","volume":"275","author":"Ichijo","year":"1997","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jbior.2012.09.006","article-title":"Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling","volume":"53","author":"Shiizaki","year":"2012","journal-title":"Adv. Biol. Regul."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jbior.2017.05.004","article-title":"The regulatory and signaling mechanisms of the ASK family","volume":"66","author":"Nishida","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1016\/j.bbagen.2016.09.028","article-title":"Pleiotropic properties of ASK1","volume":"1861","author":"Sakauchi","year":"2016","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Gen. Subj."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1006\/bbrc.1998.9749","article-title":"MAPKKK6, a Novel Mitogen-Activated Protein Kinase Kinase Kinase, That Associates with MAPKKK5","volume":"253","author":"Wang","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7522","DOI":"10.1074\/jbc.M607177200","article-title":"Apoptosis Signal-regulating Kinase (ASK) 2 Functions as a Mitogen-activated Protein Kinase Kinase Kinase in a Heteromeric Complex with ASK1","volume":"282","author":"Takeda","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.bbrc.2010.03.164","article-title":"ASK3, a novel member of the apoptosis signal-regulating kinase family, is essential for stress-induced cell death in HeLa cells","volume":"395","author":"Kaji","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/emboj.2009.32","article-title":"ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis","volume":"28","author":"Iriyama","year":"2009","journal-title":"EMBO J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.bbrc.2007.08.006","article-title":"Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling","volume":"362","author":"Ortner","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/ncomms2283","article-title":"ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK\/OSR1 signaling in the kidney","volume":"3","author":"Naguro","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1016\/j.celrep.2018.02.045","article-title":"A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress","volume":"22","author":"Watanabe","year":"2018","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1152\/physrev.00028.2011","article-title":"Mammalian MAPK Signal Transduction Pathways Activated by Stress and Inflammation: A 10-Year Update","volume":"92","author":"Kyriakis","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jbior.2017.10.003","article-title":"Regulation of ASK1 signaling by scaffold and adaptor proteins","volume":"66","author":"Rusnak","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8511","DOI":"10.1073\/pnas.96.15.8511","article-title":"Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins","volume":"96","author":"Zhang","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1172\/JCI200317790","article-title":"AIP1 mediates TNF-\u03b1\u2013induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3","volume":"111","author":"Zhang","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/jcp.10080","article-title":"Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer","volume":"191","author":"Tobiume","year":"2002","journal-title":"J. Cell. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46566","DOI":"10.1074\/jbc.M206826200","article-title":"Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2","volume":"277","author":"Song","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10442","DOI":"10.1074\/jbc.M311129200","article-title":"Activation of Apoptosis Signal-regulating Kinase 1 by Reactive Oxygen Species through Dephosphorylation at Serine 967 and 14-3-3 Dissociation","volume":"279","author":"Goldman","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37033","DOI":"10.1074\/jbc.M506771200","article-title":"Recruitment of Tumor Necrosis Factor Receptor-associated Factor Family Proteins to Apoptosis Signal-regulating Kinase 1 Signalosome Is Essential for Oxidative Stress-induced Cell Death","volume":"280","author":"Noguchi","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8152","DOI":"10.1128\/MCB.00227-07","article-title":"Thioredoxin and TRAF Family Proteins Regulate Reactive Oxygen Species-Dependent Activation of ASK1 through Reciprocal Modulation of the N-Terminal Homophilic Interaction of ASK1","volume":"27","author":"Fujino","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/onc.2009.382","article-title":"Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome","volume":"29","author":"Cockrell","year":"2009","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1074\/mcp.M115.057364","article-title":"Assembly Dynamics and Stoichiometry of the Apoptosis Signal-regulating Kinase (ASK) Signalosome in Response to Electrophile Stress","volume":"15","author":"Federspiel","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1042\/bj20030275","article-title":"Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress-induced activation of apoptosis signal-regulating kinase 1","volume":"373","author":"Song","year":"2003","journal-title":"Biochem. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1091\/mbc.e07-05-0491","article-title":"Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis","volume":"18","author":"Nadeau","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3628","DOI":"10.1091\/mbc.e09-03-0211","article-title":"REDOX Reaction at ASK1-Cys250 Is Essential for Activation of JNK and Induction of Apoptosis","volume":"20","author":"Nadeau","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24463","DOI":"10.1074\/jbc.M114.583807","article-title":"Biophysical and Structural Characterization of the Thioredoxin-binding Domain of Protein Kinase ASK1 and Its Interaction with Reduced Thioredoxin","volume":"289","author":"Kosek","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20753","DOI":"10.1074\/jbc.M116.724310","article-title":"Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1)","volume":"291","author":"Petrvalska","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1111\/febs.13893","article-title":"Cysteine residues mediate high-affinity binding of thioredoxin to ASK1","volume":"283","author":"Kylarova","year":"2016","journal-title":"FEBS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1111\/febs.15101","article-title":"The redox-active site of thioredoxin is directly involved in apoptosis signal-regulating kinase 1 binding that is modulated by oxidative stress","volume":"287","author":"Psenakova","year":"2019","journal-title":"FEBS J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/sj.onc.1210740","article-title":"G1 to S phase transition protein 1 induces apoptosis signal-regulating kinase 1 activation by dissociating 14-3-3 from ASK1","volume":"27","author":"Lee","year":"2007","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1161\/01.RES.0000022160.64355.62","article-title":"Thioredoxin Promotes ASK1 Ubiquitination and Degradation to Inhibit ASK1-Mediated Apoptosis in a Redox Activity-Independent Manner","volume":"90","author":"Liu","year":"2002","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1093\/emboj\/17.9.2596","article-title":"Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1","volume":"17","author":"Saitoh","year":"1998","journal-title":"EMBO J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1128\/MCB.20.6.2198-2208.2000","article-title":"Activation of Apoptosis Signal-Regulating Kinase 1 (ASK1) by Tumor Necrosis Factor Receptor-Associated Factor 2 Requires Prior Dissociation of the ASK1 Inhibitor Thioredoxin","volume":"20","author":"Liu","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jbior.2017.05.003","article-title":"ASK family and cancer","volume":"66","author":"Ryuno","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jbior.2017.10.011","article-title":"ASK family in cardiovascular biology and medicine","volume":"66","author":"Liu","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jbior.2017.10.007","article-title":"Physiological roles of ASK family members in innate immunity and their involvement in pathogenesis of immune diseases","volume":"66","author":"Matsuzawa","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jbior.2017.08.003","article-title":"ASK1 in neurodegeneration","volume":"66","author":"Guo","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jbior.2017.10.004","article-title":"Therapeutic application of apoptosis signal-regulating kinase 1 inhibitors","volume":"66","author":"Fujisawa","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1517\/13543776.2014.894977","article-title":"p38 MAPK inhibitors: A patent review (2012\u20132013)","volume":"24","author":"Laufer","year":"2014","journal-title":"Expert Opin. Ther. Patents"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/ki.2008.559","article-title":"Inhibition of C-jun N-terminal kinase improves insulin sensitivity but worsens albuminuria in experimental diabetes","volume":"75","author":"Ijaz","year":"2009","journal-title":"Kidney Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E2096","DOI":"10.1073\/pnas.1620813114","article-title":"Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1","volume":"114","author":"Weijman","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.str.2007.08.011","article-title":"Structural and Functional Characterization of the Human Protein Kinase ASK1","volume":"15","author":"Bunkoczi","year":"2007","journal-title":"Structure"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"eaay6318","DOI":"10.1126\/scisignal.aay6318","article-title":"Structure-based mechanism of preferential complex formation by apoptosis signal\u2013regulating kinases","volume":"13","author":"Trevelyan","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1161\/01.RES.0000130525.37646.a7","article-title":"Thioredoxin-2 Inhibits Mitochondria-Located ASK1-Mediated Apoptosis in a JNK-Independent Manner","volume":"94","author":"Zhang","year":"2004","journal-title":"Circ. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1128\/MCB.21.3.893-901.2001","article-title":"Akt Phosphorylates and Negatively Regulates Apoptosis Signal-Regulating Kinase 1","volume":"21","author":"Kim","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1038\/onc.2009.276","article-title":"PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis","volume":"28","author":"Gu","year":"2009","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1128\/MCB.01677-12","article-title":"p90 RSK2 Mediates Antianoikis Signals by both Transcription-Dependent and -Independent Mechanisms","volume":"33","author":"Jin","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1074\/jbc.M511744200","article-title":"Induction of Apoptosis by the Ste20-like Kinase SLK, a Germinal Center Kinase That Activates Apoptosis Signal-regulating Kinase and p38","volume":"281","author":"Hao","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1038\/cdd.2011.168","article-title":"Arginine methylation-dependent regulation of ASK1 signaling by PRMT1","volume":"19","author":"Cho","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1091\/mbc.E15-10-0738","article-title":"Cross-talk between Arg methylation and Ser phosphorylation modulates apoptosis signal\u2013regulating kinase 1 activation in endothelial cells","volume":"27","author":"Chen","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/S1097-2765(00)80283-X","article-title":"ASK1 Is Essential for JNK\/SAPK Activation by TRAF2","volume":"2","author":"Nishitoh","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"34541","DOI":"10.1074\/jbc.M807219200","article-title":"Murine Protein Serine\/Threonine Kinase 38 Activates Apoptosis Signal-regulating Kinase 1 via Thr838 Phosphorylation","volume":"283","author":"Jung","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13481","DOI":"10.1074\/jbc.M809740200","article-title":"JAK2 and SHP2 Reciprocally Regulate Tyrosine Phosphorylation and Stability of Proapoptotic Protein ASK1","volume":"284","author":"Yu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5559","DOI":"10.1074\/jbc.M512338200","article-title":"SOCS1 Inhibits Tumor Necrosis Factor-induced Activation of ASK1-JNK Inflammatory Signaling by Mediating ASK1 Degradation","volume":"281","author":"He","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1038\/sj.onc.1207668","article-title":"Negative control of apoptosis signal-regulating kinase 1 through phosphorylation of Ser-1034","volume":"23","author":"Fujii","year":"2004","journal-title":"Oncogene"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/bs.pmch.2020.02.001","article-title":"Discovery and development of ASK1 inhibitors","volume":"59","author":"Brys","year":"2020","journal-title":"Prog. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s00109-020-01878-y","article-title":"ASK1 inhibition: A therapeutic strategy with multi-system benefits","volume":"98","author":"Ogier","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00109-018-01739-9","article-title":"Pathological role of apoptosis signal-regulating kinase 1 in human diseases and its potential as a therapeutic target for cognitive disorders","volume":"97","author":"Cheon","year":"2019","journal-title":"J. Mol. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.3390\/ijms15022119","article-title":"Apoptosis Signal Regulating Kinase 1 (ASK1): Potential as a Therapeutic Target for Alzheimer\u2019s Disease","volume":"15","author":"Song","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. Molecules, 25.","DOI":"10.3390\/molecules25245789"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/sj.cdd.4401528","article-title":"Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation","volume":"12","author":"Kadowaki","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3233\/JAD-170645","article-title":"Role of ASK1\/p38 Cascade in a Mouse Model of Alzheimer\u2019s Disease and Brain Aging","volume":"61","author":"Hasegawa","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1248\/bpb.b20-00409","article-title":"Elaidic Acid Potentiates Extracellular ATP-Induced Apoptosis via the P2X7-ROS-ASK1-p38 Axis in Microglial Cell Lines","volume":"43","author":"Hirata","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","article-title":"Parkinson\u2019s disease","volume":"386","author":"Kalia","year":"2015","journal-title":"Lancet"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pan, J., Li, H., Zhang, B., Xiong, R., Zhang, Y., Kang, W.-Y., Chen, W., Zhao, Z.-B., and Chen, S.-D. (2015). Small Peptide Inhibitor of JNK3 Protects Dopaminergic Neurons from MPTP Induced Injury via Inhibiting the ASK1-JNK3 Signaling Pathway. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119204"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.neurobiolaging.2014.07.034","article-title":"Apoptosis signal-regulating kinase 1 modulates the phenotype of \u03b1-synuclein transgenic mice","volume":"36","author":"Lee","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S1474-4422(08)70117-0","article-title":"Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson\u2019s disease: A case-control study","volume":"7","author":"Healy","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"9691","DOI":"10.1073\/pnas.0409635102","article-title":"Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death","volume":"102","author":"Junn","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.abb.2011.07.016","article-title":"Blocking Daxx trafficking attenuates neuronal cell death following ischemia\/reperfusion in rat hippocampus CA1 region","volume":"515","author":"Niu","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"147310","DOI":"10.1016\/j.brainres.2021.147310","article-title":"RIPK1 inhibitor ameliorates the MPP(+)\/MPTP-induced Parkinson\u2019s disease through the ASK1\/JNK signalling pathway","volume":"1757","author":"Liu","year":"2021","journal-title":"Brain Res."},{"key":"ref_71","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (1993). Huntington Disease. GeneReviews((R)), University of Washington."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00109-007-0299-6","article-title":"ASK1 and MAP2K6 as modifiers of age at onset in Huntington\u2019s disease","volume":"86","author":"Arning","year":"2008","journal-title":"J. Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1101\/gad.992302","article-title":"ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats","volume":"16","author":"Nishitoh","year":"2002","journal-title":"Genes Dev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.neuroscience.2009.07.048","article-title":"Inhibition of apoptosis signal-regulating kinase 1 reduces endoplasmic reticulum stress and nuclear huntingtin fragments in a mouse model of Huntington disease","volume":"163","author":"Cho","year":"2009","journal-title":"Neuroscience"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.expneurol.2008.10.008","article-title":"Implication of the JNK pathway in a rat model of Huntington\u2019s disease","volume":"215","author":"Perrin","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.bbrc.2013.08.103","article-title":"Apoptosis signal-regulating kinase-1 aggravates ROS-mediated striatal degeneration in 3-nitropropionic acid-infused mice","volume":"441","author":"Cho","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1101\/gad.1640108","article-title":"ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1","volume":"22","author":"Nishitoh","year":"2008","journal-title":"Genes Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.neulet.2018.09.040","article-title":"Activation of the unfolded protein response in canine degenerative myelopathy","volume":"687","author":"Yokota","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/hmg\/ddv467","article-title":"The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis","volume":"25","author":"Fujisawa","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1161\/HYPERTENSIONAHA.119.14556","article-title":"Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension","volume":"76","author":"Meijles","year":"2020","journal-title":"Hypertension"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.bbrc.2004.12.002","article-title":"CaMKII activates ASK1 and NF-kappaB to induce cardiomyocyte hypertrophy","volume":"327","author":"Kashiwase","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"100852","DOI":"10.1016\/j.ijcha.2021.100852","article-title":"Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways","volume":"36","author":"Huang","year":"2021","journal-title":"IJC Hearth Vasc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.2337\/db05-1187","article-title":"Impact of Mitochondrial Reactive Oxygen Species and Apoptosis Signal-Regulating Kinase 1 on Insulin Signaling","volume":"55","author":"Imoto","year":"2006","journal-title":"Diabetes"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"174402","DOI":"10.1016\/j.ejphar.2021.174402","article-title":"Apocynin attenuates diabetic cardiomyopathy by suppressing ASK1-p38\/JNK signaling","volume":"909","author":"Ding","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"675","DOI":"10.3389\/fphys.2021.651105","article-title":"Thioredoxin-1 Is a Target to Attenuate Alzheimer-Like Pathology in Diabetic Encephalopathy by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress","volume":"12","author":"Guo","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ren, X., Lv, J., Fu, Y., Zhang, N., Zhang, C., Dong, Z., Chudhary, M., Zhong, S., Kong, L., and Kong, H. (2021). Upregulation of thioredoxin contributes to inhibiting diabetic hearing impairment. Diabetes Res. Clin. Pract., 179.","DOI":"10.1016\/j.diabres.2021.109025"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"49220","DOI":"10.1074\/jbc.M207325200","article-title":"Liver protection from apoptosis requires both blockage of initiator caspase activities and inhibition of ASK1\/JNK pathway via glutathione S-transferase regulation","volume":"277","author":"Gilot","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1053\/j.gastro.2008.07.006","article-title":"Deletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation","volume":"135","author":"Nakagawa","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.taap.2015.03.019","article-title":"Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury","volume":"286","author":"Xie","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"6273","DOI":"10.18632\/oncotarget.14059","article-title":"Adenosine 5\u2032-monophosphate blocks acetaminophen toxicity by increasing ubiquitination-mediated ASK1 degradation","volume":"8","author":"Yang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1161\/HYPERTENSIONAHA.108.112292","article-title":"Olmesartan Prevents Cardiovascular Injury and Hepatic Steatosis in Obesity and Diabetes, Accompanied by Apoptosis Signal Regulating Kinase-1 Inhibition","volume":"52","author":"Yamamoto","year":"2008","journal-title":"Hypertension"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.jhep.2016.02.002","article-title":"Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis","volume":"64","author":"Xiang","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nm.4290","article-title":"Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates","volume":"23","author":"Wang","year":"2017","journal-title":"Nat. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/hep.29514","article-title":"The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial","volume":"67","author":"Loomba","year":"2017","journal-title":"Hepatology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"F1263","DOI":"10.1152\/ajprenal.00211.2014","article-title":"ASK1\/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney","volume":"307","author":"Ma","year":"2014","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1016\/j.molimm.2007.11.013","article-title":"Role of apoptosis signal-regulating kinase 1 in complement-mediated glomerular epithelial cell injury","volume":"45","author":"Ren","year":"2008","journal-title":"Mol. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.2337\/db15-0384","article-title":"ASK1 Inhibitor Halts Progression of Diabetic Nephropathy inNos3-Deficient Mice","volume":"64","author":"Tesch","year":"2015","journal-title":"Diabetes"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4522","DOI":"10.1111\/jcmm.13705","article-title":"ASK1 inhibitor treatment suppresses p38\/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis","volume":"22","author":"Amos","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1681\/ASN.2018121231","article-title":"Effects of Selonsertib in Patients with Diabetic Kidney Disease","volume":"30","author":"Chertow","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1182\/blood-2011-12-399808","article-title":"ASK1 promotes apoptosis of normal and malignant plasma cells","volume":"120","author":"Lin","year":"2012","journal-title":"Blood"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"27408","DOI":"10.18632\/oncotarget.8478","article-title":"Apoptosis signal-regulating kinase 1 mediates the inhibitory effect of hepatocyte nuclear factor-4\u03b1 on hepatocellular carcinoma","volume":"7","author":"Jiang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1128\/MCB.06798-11","article-title":"SCO2 Induces p53-Mediated Apoptosis by Thr845 Phosphorylation of ASK-1 and Dissociation of the ASK-1-Trx Complex","volume":"33","author":"Madan","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"19878","DOI":"10.1073\/pnas.0908458106","article-title":"DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis","volume":"106","author":"Xie","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cellsig.2016.11.018","article-title":"ASK1 regulates the survival of neuroblastoma cells by interacting with TLX and stabilizing HIF-1\u03b1","volume":"30","author":"Sobhan","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1073\/pnas.1011418108","article-title":"Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer","volume":"108","author":"Hayakawa","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.bcp.2012.11.021","article-title":"Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma","volume":"85","author":"Tzeng","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"75155","DOI":"10.18632\/oncotarget.12090","article-title":"Apoptosis signal-regulating kinase 1 exhibits oncogenic activity in pancreatic cancer","volume":"7","author":"Luo","year":"2016","journal-title":"Oncotarget"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"687033","DOI":"10.3389\/fphar.2021.687033","article-title":"Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study","volume":"12","author":"Yan","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1002\/jcp.30009","article-title":"PM2.5 facilitates IL-6 production in human osteoarthritis synovial fibroblasts via ASK1 activation","volume":"236","author":"Liu","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/ar2531","article-title":"Developments in the clinical understanding of osteoarthritis","volume":"11","author":"Felson","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"4405","DOI":"10.2174\/0929867321666140915143040","article-title":"p38 MAPK: A Potential Target of Chronic Pain","volume":"21","author":"Lin","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Giraud, F., Pereira, E., Anizon, F., and Moreau, P. (2021). Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors. Molecules, 26.","DOI":"10.3390\/molecules26092696"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1002\/emmm.201000103","article-title":"Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway","volume":"2","author":"Guo","year":"2010","journal-title":"EMBO Mol. Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.intimp.2010.06.023","article-title":"Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K\/BxN serum-induced arthritis","volume":"10","author":"Mnich","year":"2010","journal-title":"Int. Immunopharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.bcp.2018.01.041","article-title":"Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis","volume":"151","author":"Nygaard","year":"2018","journal-title":"Biochem. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13395\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:47:00Z","timestamp":1760168820000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,13]]},"references-count":115,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222413395"],"URL":"https:\/\/doi.org\/10.3390\/ijms222413395","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,13]]}}}