{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:04:24Z","timestamp":1790229864770,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder, and ferroptosis-an iron-dependent form of regulated cell death-has been increasingly implicated in AD-related neuronal loss. However, the causal relationship between specific ferroptosis-related genes and AD, particularly within defined neuronal subtypes, remains incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated two-sample Mendelian Randomization (MR) with single-cell expression quantitative trait locus (eQTL) analysis, followed by in vivo validation using AAV9-c-fos-mediated MAPK3 knockdown in APP\/PS1 transgenic mice and in vitro validation using siRNA-mediated MAPK3 silencing in A\u03b2-treated HT22 neurons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR analysis of large-scale genetic datasets identified seven ferroptosis-related genes with causal associations with AD. Single-cell eQTL MR prioritized MAPK3 as a significant risk factor specifically within excitatory neurons. AAV9-c-fos-mediated MAPK3 knockdown in APP\/PS1 mice significantly ameliorated cognitive deficits in the Morris water maze. Mechanistically, MAPK3 knockdown inhibited aberrant CaMKII phosphorylation, activated the Nrf2-GPX4 antioxidant axis (upregulation of GPX4, HO-1, and FTH1; downregulation of ACSL4 and KEAP1), and reestablished the Bax\/Bcl-2 equilibrium, thereby reducing both ferroptosis and apoptosis. These effects were reproduced in A\u03b2-treated HT22 neurons following siRNA-mediated MAPK3 silencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our findings identify MAPK3 in excitatory neurons as a potential causal link between genetic risk and AD pathogenesis, bridging population-level genetic risk and cellular vulnerability. Targeting the MAPK3-CaMKII-Nrf2 axis may represent a promising, cell-type-specific therapeutic strategy for AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1868908","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:42:55Z","timestamp":1790228575000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MAPK3 as a ferroptosis driver in excitatory neurons in Alzheimer\u2019s disease: from genetic causal inference to in vivo functional validation"],"prefix":"10.3389","volume":"18","author":[{"given":"Xiaoqiong","family":"An","sequence":"first","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Key Laboratory of Human Brain Bank for Functions and Diseases of Department of Education of Guizhou Province, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Department of Laboratory Medicine, The Second People\u2019s Hospital of Guizhou Province, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changge","family":"Wei","sequence":"additional","affiliation":[{"name":"Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University","place":["Guizhou, China"]},{"name":"School of Pharmaceutical Sciences, Guizhou Medical University","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manni","family":"Cao","sequence":"additional","affiliation":[{"name":"Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University","place":["Guizhou, China"]},{"name":"School of Pharmaceutical Sciences, Guizhou Medical University","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwei","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University","place":["Guizhou, China"]},{"name":"Department of Pharmacology, School of Basic Medicine, Guizhou Medical University","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfeng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang","place":["Guizhou, China"]},{"name":"Key Laboratory of Human Brain Bank for Functions and Diseases of Department of Education of Guizhou Province, Guizhou Medical University, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenkui","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The Second People\u2019s Hospital of Guizhou Province, Guiyang","place":["Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.3390\/molecules25245789","article-title":"Comprehensive review on alzheimer\u2019s disease: Causes and treatment.","volume":"25","author":"Breijyeh","year":"2020","journal-title":"Molecules"},{"key":"B2","doi-asserted-by":"publisher","first-page":"590","DOI":"10.3390\/pathogens14060590","article-title":"Latency-associated nuclear antigen (LANA) promotes ferroptosis by suppressing NRF2\/GPX4 and upregulating MDM2.","volume":"14","author":"Cao","year":"2025","journal-title":"Pathogens"},{"key":"B3","first-page":"249","article-title":"Postnatal neuronal nogo-a knockdown decreased the message of glutamatergic synaptic proteins.","volume":"67","author":"Case","year":"2024","journal-title":"J. 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