{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:12:41Z","timestamp":1788351161894,"version":"build-2803163510"},"reference-count":73,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Background: Hypoxia-induced oxidative stress and ferroptosis contribute to blood\u2013brain barrier dysfunction and neurovascular injury associated with ischemic stroke and neurodegenerative diseases. Luteolin, a naturally occurring flavonoid with potent antioxidant and anti-inflammatory activities, has emerged as a potential neuroprotective agent; however, its effects on hypoxia-induced ferroptosis in brain microvascular endothelial cells remain unclear. This study investigated the protective effects of luteolin and its association with changes in the PPAR\u03b3\/FABP5\/ALOX15 signaling pathway during hypoxia-induced ferroptotic injury. Methods: Human brain microvascular endothelial cells (HBEC-5i) were exposed to cobalt chloride (CoCl2) to establish an in vitro hypoxia model and subsequently treated with luteolin. Cell viability was assessed using the MTT assay. Intracellular Fe2+ accumulation, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH\/GSSG) levels were determined using biochemical assays. The expression of ferroptosis- and hypoxia-related proteins, including GPX4, ALOX15, FABP5, PPAR\u03b3, HIF-1\u03b1, and VEGF, was evaluated by Western blotting. Results: CoCl2-induced hypoxia significantly reduced cell viability and increased intracellular Fe2+ accumulation, ROS generation, lipid peroxidation, and ferroptosis-associated signaling in HBEC-5i cells. Hypoxic conditions upregulated ALOX15 and FABP5 expression while suppressing GPX4 and PPAR\u03b3 levels. Luteolin treatment markedly attenuated these effects by restoring GSH\/GSSG homeostasis, enhancing GPX4 expression, reducing ALOX15-mediated lipid peroxidation, and suppressing HIF-1\u03b1 and VEGF expression. In addition, luteolin modulated the PPAR\u03b3\/FABP5 signaling pathway, suggesting its involvement in the regulation of hypoxia-induced ferroptosis. Conclusions: Luteolin attenuates hypoxia-induced ferroptosis-associated changes in human brain microvascular endothelial cells by restoring redox homeostasis and is associated with coordinated modulation of the PPAR\u03b3\/FABP5\/ALOX15 pathway. These findings extend previous reports of the anti-ferroptotic effects of luteolin by providing evidence in brain microvascular endothelial cells under hypoxia-mimetic stress.<\/jats:p>","DOI":"10.3390\/biomedicines14091981","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:57:23Z","timestamp":1788346643000},"page":"1981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Luteolin Attenuates Hypoxia-Induced Ferroptosis in Human Brain Microvascular Endothelial Cells Through Modulation of the PPAR\u03b3\/FABP5\/ALOX15 Signaling Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3292-1851","authenticated-orcid":false,"given":"Sirirak","family":"Mukem","sequence":"first","affiliation":[{"name":"School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Patcharakorn","family":"Kiatamornrak","sequence":"additional","affiliation":[{"name":"Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Critical Care Nephrology, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9129-2082","authenticated-orcid":false,"given":"Saowaros","family":"Suwansa-ard","sequence":"additional","affiliation":[{"name":"School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4558, Australia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-8477","authenticated-orcid":false,"given":"Tipsuda","family":"Thongbuakaew","sequence":"additional","affiliation":[{"name":"School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,2]]},"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":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nchembio.2238","article-title":"Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis","volume":"13","author":"Kagan","year":"2017","journal-title":"Nat. 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