{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T23:06:26Z","timestamp":1770246386718,"version":"3.49.0"},"reference-count":101,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T00:00:00Z","timestamp":1770163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Psychiatry and Psychology at the Mayo Clinic, Arizona"},{"name":"Edli Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Post-COVID syndrome comprises persistent neuropsychiatric manifestations for more than 12 weeks after recovery from acute SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. Ferroptosis, an iron-dependent form of cell death with three hallmarks, iron dysregulation, antioxidant failure, and lipid peroxidation, seems to be involved in COVID-19\/post-COVID-19 pathophysiology. Here, we administered the SARS-CoV-2 spike protein S1 subunit intranasally to K18-hACE2 transgenic mice and quantified ferroptotic marker protein expression in four brain regions (hippocampus, prefrontal cortex, cerebellum, and olfactory bulb) at 2, 6, and 12 weeks post-administration, alongside ultrastructural assessment by transmission electron microscopy (TEM) that was limited to the hippocampus and prefrontal cortex. Two-way ANOVA revealed region- and time-dependent modulation of iron-handling, antioxidant, and lipid peroxidation markers. In the hippocampus, FPN1 was significantly increased at 2 weeks, while TFR1 showed a time-dependent pattern without significant week-specific differences. In the prefrontal cortex, DMT1 significantly increased at 2 weeks, and GPx4 showed an overall treatment effect with a trend of increase at 6 weeks. The cerebellum exhibited early increases in FPN1 and GPx4 and a delayed increase in MDA-conjugated proteins. In the olfactory bulb, FPN1 increased at 12 weeks, with GPx4 showing an overall treatment effect and an early trend of decrease. TEM identified ferroptosis-consistent features in the hippocampus and prefrontal cortex at all time points. These findings suggest that spike protein exposure may be associated with time-dependent and brain-region-specific alterations of ferroptosis-related markers. These preliminary findings are based on a limited sample size, which needs further research to elucidate the clinical implication and to study the mechanism in more depth as well as future validation with pharmacological inhibitors.<\/jats:p>","DOI":"10.3390\/ijms27031526","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T10:02:57Z","timestamp":1770199377000},"page":"1526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SARS-CoV-2 Spike Protein Induces Time-Dependent and Brain-Region-Specific Alterations in Ferroptosis Markers: A Preliminary Study in K18-hACE2 Mice"],"prefix":"10.3390","volume":"27","author":[{"given":"Asmaa","family":"Yehia","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ 58054, USA"},{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6845-141X","authenticated-orcid":false,"given":"Chirine","family":"Toufaily","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ 58054, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8793-5356","authenticated-orcid":false,"given":"Dalia M.","family":"Abdel Ghaffar","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gehan","family":"El Wakeel","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Basic Dental Sciences, Faculty of Dentistry, The Hashemite University, Zarqa 13115, Jordan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0107-7320","authenticated-orcid":false,"given":"Mohamed","family":"Adel","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura National University, Gamasa 35712, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abeer F.","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0652-0862","authenticated-orcid":false,"given":"Osama A.","family":"Abulseoud","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ 58054, USA"},{"name":"Department of Psychiatry and Psychology, Mayo Clinic Arizona, Phoenix, AZ 85054, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev-cancerbio-030518-055844","article-title":"The hallmarks of ferroptosis","volume":"3","author":"Dixon","year":"2019","journal-title":"Annu. 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