SARS-CoV-2 Spike Protein Induces Time-Dependent and Brain-Region-Specific Alterations in Ferroptosis Markers: A Preliminary Study in K18-hACE2 Mice

DOI record: { "DOI": "10.3390/ijms27031526", "ISSN": [ "1422-0067" ], "URL": "http://dx.doi.org/10.3390/ijms27031526", "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>", "alternative-id": [ "ijms27031526" ], "author": [ { "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" } ], "family": "Yehia", "given": "Asmaa", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-6845-141X", "affiliation": [ { "name": "Department of Neuroscience, Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine, Phoenix, AZ 58054, USA" } ], "authenticated-orcid": false, "family": "Toufaily", "given": "Chirine", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-8793-5356", "affiliation": [ { "name": "Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt" } ], "authenticated-orcid": false, "family": "Abdel Ghaffar", "given": "Dalia M.", "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" } ], "family": "El Wakeel", "given": "Gehan", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-0107-7320", "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" } ], "authenticated-orcid": false, "family": "Adel", "given": "Mohamed", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt" } ], "family": "Mostafa", "given": "Abeer F.", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-0652-0862", "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" } ], "authenticated-orcid": false, "family": "Abulseoud", "given": "Osama A.", "sequence": "additional" } ], "container-title": "International Journal of Molecular Sciences", "container-title-short": "IJMS", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2026, 2, 4 ] ], "date-time": "2026-02-04T10:02:57Z", "timestamp": 1770199377000 }, "deposited": { "date-parts": [ [ 2026, 2, 4 ] ], "date-time": "2026-02-04T10:03:45Z", "timestamp": 1770199425000 }, "funder": [ { "name": "Department of Psychiatry and Psychology at the Mayo Clinic, Arizona" }, { "name": "Edli Foundation" } ], "indexed": { "date-parts": [ [ 2026, 2, 4 ] ], "date-time": "2026-02-04T23:06:26Z", "timestamp": 1770246386718, "version": "3.49.0" }, "is-referenced-by-count": 0, "issue": "3", "issued": { "date-parts": [ [ 2026, 2, 4 ] ] }, "journal-issue": { "issue": "3", "published-online": { "date-parts": [ [ 2026, 2 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 2, 4 ] ], "date-time": "2026-02-04T00:00:00Z", "timestamp": 1770163200000 } } ], "link": [ { "URL": "https://www.mdpi.com/1422-0067/27/3/1526/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "1526", "prefix": "10.3390", "published": { "date-parts": [ [ 2026, 2, 4 ] ] }, "published-online": { "date-parts": [ [ 2026, 2, 4 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.1016/j.cell.2012.03.042", "article-title": "Ferroptosis: An iron-dependent form of nonapoptotic cell death", "author": "Dixon", "doi-asserted-by": "crossref", "first-page": "1060", "journal-title": "Cell", "key": "ref_1", "volume": "149", "year": "2012" }, { "DOI": "10.1146/annurev-cancerbio-030518-055844", "article-title": "The hallmarks of ferroptosis", "author": "Dixon", "doi-asserted-by": "crossref", "first-page": "35", "journal-title": "Annu. 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