{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T07:30:36Z","timestamp":1793345436069,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012579","name":"Natural Science Foundation of Qinghai Province","doi-asserted-by":"publisher","award":["2025\u2010ZJ\u2010748"],"award-info":[{"award-number":["2025\u2010ZJ\u2010748"]}],"id":[{"id":"10.13039\/501100012579","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974283"],"award-info":[{"award-number":["81974283"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic high\u2010altitude hypoxia impairs hippocampal memory, yet population\u2010level dose\u2013response relationships and the molecular mechanisms linking hypoxic stress to energy metabolic collapse remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a cross\u2010sectional study of 2819 residents (living at altitudes between 3000 and 5000\u2009m). In parallel, we established a rat model of sustained hypobaric hypoxia (6000\u2009m, 1\u201328\u2009days) and applied pharmacological intervention using the JNK inhibitor JNK\u2010IN\u20108. Metabolomic profiling, transmission electron microscopy, and molecular analyses were performed to assess metabolic reprogramming, mitochondrial ultrastructure, and signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Residents at &gt;\u20094000\u2009m exhibited 91% higher memory impairment risk. Chronic hypoxia activated JNK\u2010p53\u2010Bim signaling, driving mitophagy\u2010to\u2010apoptosis transition, mitochondrial cristae disruption, and 73% ATP depletion by Day 28. JNK\u2010IN\u20108 partially restored ATP and suppressed p53. HIF\u20102\u03b1\/PHD2 colocalization indicated parallel adaptive signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Chronic hypoxia induces memory impairment via JNK\u2010mediated mitochondrial dysfunction. JNK inhibition offers therapeutic potential, while concurrent HIF\u20102\u03b1\/PHD2 activation suggests a complex balance between hypoxic injury and adaptation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70986","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T12:30:56Z","timestamp":1781699456000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["High\u2010Altitude Hypoxia Activates\n                    <scp>JNK<\/scp>\n                    \u2010p53 Signaling: Linking Hippocampal Energy Crisis to Cognitive Impairment"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8841-7032","authenticated-orcid":false,"given":"Guisheng","family":"Hao","sequence":"first","affiliation":[{"name":"Research Center for High Altitude Medicine Qinghai University, Key Laboratory of the Ministry of High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Applied Basic Research in High Altitude Medicine  Xining China"},{"name":"Qinghai Provincial People's Hospital  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengzhong","family":"Bai","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine Qinghai University, Key Laboratory of the Ministry of High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Applied Basic Research in High Altitude Medicine  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0651-6758","authenticated-orcid":false,"given":"Wenjuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Qinghai Provincial People's Hospital  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0943-314X","authenticated-orcid":false,"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Tsinghua Changgung Hospital, School of Clinical Medicine Tsinghua University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine Qinghai University, Key Laboratory of the Ministry of High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Applied Basic Research in High Altitude Medicine  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2189-2987","authenticated-orcid":false,"given":"Guoen","family":"Jin","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine Qinghai University, Key Laboratory of the Ministry of High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Applied Basic Research in High Altitude Medicine  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-7060","authenticated-orcid":false,"given":"Ri\u2010Li","family":"Ge","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine Qinghai University, Key Laboratory of the Ministry of High Altitude Medicine, Laboratory for High Altitude Medicine of Qinghai Province, Key Laboratory of Applied Basic Research in High Altitude Medicine  Xining China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2102463118"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2024.114663"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13869"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/wad.0000000000000647"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3233\/jad\u2010240163"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/2047\u20109158\u20103\u20107"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.12677\/ap.2023.138439"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/3063899"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnint.2021.792863"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2415358122"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom14020243"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13111794"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357\u2010024\u201001118\u2010y"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00248"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020\u2010022\u201000471\u2010y"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.13452\/j.cnki.jqmc.2025.02.006"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2023.1281581"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0960327116689714"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.952399"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.617143"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2024.1330596"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.784045"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.13996"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010022\u201001260\u20106"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1089\/ham.2020.0127"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9081802"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.01.17.575386"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109\u2010019\u201001856\u2010z"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102190"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336918.2024.2316576"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.2980"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1178"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010025\u201002176\u20100"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2023.1216947"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2023.1277375"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11033\u2010023\u201008641\u20109"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010021\u201004004\u20104"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms251910446"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/md.0000000000041479"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232214094"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010023\u201000602\u2010x"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101558"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.94"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14897"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578\u2010025\u201001420\u2010y"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/4163188"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.70986","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cns.70986","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.70986","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T06:32:06Z","timestamp":1793341926000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cns.70986"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/cns.70986"],"URL":"https:\/\/doi.org\/10.1002\/cns.70986","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"2026-03-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70986"}}