{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:15:32Z","timestamp":1790079332528,"version":"4.0.1"},"reference-count":20,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"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":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Elevated homocysteine (Hcy) is a potent instigator of cerebrovascular endothelial injury, yet effective preventive interventions are scarce. This study identifies the anesthetic etomidate as a protective agent against Hcy\u2010mediated damage in human brain microvascular endothelial cells (HBMVECs) and delineates its mechanism of action. We found that Hcy triggers activation of the PERK\u2010eIF2\u03b1\u2010ATF4 signaling axis, which contributes to a pathogenic cascade. This endoplasmic reticulum (ER) stress response was the pivotal event, simultaneously driving oxidative stress via transcriptional upregulation of NOX2 and disrupting autophagic flux. The consequent redox and proteostatic failure directly precipitated mitochondrial dysfunction and ultimately, cytotoxic cell death. Pre\u2010treatment with etomidate prevented this entire injury sequence. Its core mechanism is the specific inhibition of the PERK\u2010eIF2\u03b1\u2010ATF4 pathway, which reduces oxidative burden in etomidate\u2010pretreated cells by suppressing NOX2\u2010driven ROS generation rather than through direct ROS scavenging. The critical dependence on this target was confirmed when pharmacologic PERK activation abolished etomidate's protective effects. We conclude that etomidate safeguards endothelial integrity by suppressing a central ER stress pathway, thereby coordinately normalizing redox state and autophagy to preserve mitochondrial and cellular function. This work defines a novel, non\u2010anesthetic role for etomidate and nominates PERK inhibition as a strategic approach for preventing vascular injury in hyperhomocysteinemia.<\/jats:p>","DOI":"10.1002\/jbt.71003","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T17:57:08Z","timestamp":1784138228000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Etomidate Prevents Homocysteine\u2011Induced Endothelial Dysfunction by Suppressing PERK\u2011eIF2\u03b1\u2011ATF4 Signaling, Oxidative Stress, Mitochondrial Injury, and Autophagic Dysregulation"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6985-8090","authenticated-orcid":false,"given":"Mingguan","family":"Song","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Second People's Hospital of Mudanjiang City Mudanjiang Heilongjiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology Second People's Hospital of Mudanjiang City Mudanjiang Heilongjiang 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