{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:49:39Z","timestamp":1791946179272,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The molecular mechanisms underlying neurodegenerative diseases are not fully understood, but oxidative stress is known to play a central role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). In this study, we developed a method to induce gradual oxidative stress in induced pluripotent stem cell (iPSC)\u2010derived motor neurons and cortical excitatory neurons by omitting antioxidants in the media, aiming to create a platform for studying oxidative stress\u2010dependent neuronal damage in neurodegenerative diseases. Neuroprotective effects in this platform were observed with edaravone, an approved ALS medicine, in iPSC\u2010derived motor neurons, suggesting its potential for ALS drug evaluation. The oxidative stress\u2010induced neuronal damage was accompanied by increased lipid peroxidation, and it was suppressed by ferroptosis inhibitors and an iron\u2010specific chelator, suggesting that neurons died through ferroptosis. Furthermore, through a compound screen, a cholesterol biosynthesis inhibitor, AY 9944, was identified as being capable of inhibiting neuronal damage induced by oxidative stress. Additionally, neuroprotective activity was observed with 7\u2010dehydrocholesterol, an immediate precursor of cholesterol, while the efficacy of AY 9944 was compromised by knockout of the\n                    <jats:italic>EBP<\/jats:italic>\n                    gene, which encodes an enzyme involved in cholesterol biosynthesis. These findings suggest the involvement of ferroptosis in the progression of neurodegenerative diseases and the inhibition of ferroptosis by modulating the cholesterol biosynthesis pathway, providing potential insights for drug development.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70246-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70246","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T05:29:07Z","timestamp":1759123747000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neuronal Damage Induced by Gradual Oxidative Stress in i\n                    <scp>PSC<\/scp>\n                    \u2010Derived Neurons: Implications for Ferroptosis Involvement and\n                    <scp>ALS<\/scp>\n                    Drug Evaluation"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5646-059X","authenticated-orcid":false,"given":"Hayato","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Bio Science &amp; Engineering Laboratories FUJIFILM Corporation  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Suzuki\u2010Masuyama","sequence":"additional","affiliation":[{"name":"Bio Science &amp; Engineering Laboratories FUJIFILM Corporation  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4528-9772","authenticated-orcid":false,"given":"Hirokazu","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Bio Science &amp; Engineering Laboratories FUJIFILM Corporation  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kato","sequence":"additional","affiliation":[{"name":"Bio Science &amp; Engineering Laboratories FUJIFILM Corporation  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7574-750X","authenticated-orcid":false,"given":"Setsu","family":"Endoh\u2010Yamagami","sequence":"additional","affiliation":[{"name":"Bio Science &amp; Engineering Laboratories FUJIFILM Corporation  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.P071639"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70219-4"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2024.3733"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101619"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2009.11.018"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01024-z"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-5949.2009.00116.x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1017\/cjn.2016.284"},{"key":"e_1_2_10_10_1","first-page":"6","article-title":"Neurobasal Medium\/B27 Supplement: A New Serum Free Medium Combination for Survival of Neuron","volume":"16","author":"Brewer G. 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