{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T18:24:23Z","timestamp":1787595863213,"version":"build-2736575974"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hebei Province Natural Science Foundation Project","award":["H2020423042"],"award-info":[{"award-number":["H2020423042"]}]},{"name":"Hebei Province Natural Science Foundation Project","award":["2022090"],"award-info":[{"award-number":["2022090"]}]},{"name":"Hebei Provincial Administration of Traditional Chinese Medicine Research Project","award":["B2025067"],"award-info":[{"award-number":["B2025067"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Tanshinone IIA (TSA) is the core liposoluble active component of\n                      <jats:italic>Salvia miltiorrhiza<\/jats:italic>\n                      , a traditional Chinese medicine, and exhibits multiple pharmacological activities including anti-inflammation, anti-oxidation, anti-apoptosis and mitochondrial function improvement. Studies have confirmed that TSA can ameliorate cognitive function in rats with vascular dementia (VaD) by alleviating cerebral ischemic injury, inhibiting neuroinflammation, protecting the blood-brain barrier and other pathways. However, it has not been reported whether TSA exerts its neuroprotective effect by regulating the cuproptosis pathway. Focusing on cuproptosis, this study investigated the effects of TSA on cognitive impairment, neuronal injury and cuproptosis-related mechanisms in a rat model of VaD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A rat model of VaD was established by permanent bilateral common carotid artery ligation (2-VO), and the model rats were treated with TSA. The cognitive impairment of VaD rats was evaluated by the Morris water maze test. Hematoxylin-eosin (HE) staining and Nissl staining were used to detect neuronal injury and loss in the hippocampus of VaD rats. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria in the hippocampus; Western blot (WB) assay was adopted to detect the expression levels of cuproptosis-related proteins, including solute carrier family 31 member 1 (SLC31A1), ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS) and dihydrolipoamide transacetylase (DLAT).In vitro, an oxygen-glucose deprivation\/reoxygenation (OGD\/R) model was established in HT-22 cells to evaluate the effects of TSA on cell viability (CCK-8), intracellular reactive oxygen species (ROS) levels, and copper accumulation (Coppersensor-1 staining), further validating the involvement of copper homeostasis in TSA-mediated neuroprotection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The results revealed that TSA markedly alleviated cognitive dysfunction and neuronal damage in VaD rats. It also reversed the cuproptosis-related abnormal changes in the brain of VaD rats, and modulated the expression of SLC31A1\/FDX1 pathway proteins. In vitro, TSA protected HT-22 cells from OGD\/R-induced injury by reducing oxidative stress and copper accumulation.These changes were associated with amelioration of copper overload and mitochondrial damage, suggesting that TSA may exert neuroprotection partially through the regulation of cuproptosis-related pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TSA effectively alleviated cognitive impairment and neuronal injury in VaD rats, and exerted neuroprotective effects both in vivo and in vitro by attenuating copper-dependent cytotoxic stress, preserving mitochondrial integrity, and modulating the SLC31A1\/FDX1 axis. This study provides a new perspective and theoretical basis for the future development of targeted drugs for VaD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0356885","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:31:41Z","timestamp":1787592701000},"page":"e0356885","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tanshinone IIA attenuates cognitive impairment in vascular dementia rats by modulating copper homeostasis via the SLC31A1\/FDX1 axis"],"prefix":"10.1371","volume":"21","author":[{"given":"Hongxiao","family":"Lv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0369-5032","authenticated-orcid":true,"given":"Wentao","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"pone.0356885.ref001","doi-asserted-by":"crossref","first-page":"102278","DOI":"10.1016\/j.arr.2024.102278","article-title":"Vascular dementia: from pathobiology to emerging perspectives","volume":"96","author":"AE Morgan","year":"2024","journal-title":"Ageing Res Rev"},{"key":"pone.0356885.ref002","doi-asserted-by":"crossref","first-page":"101734","DOI":"10.1016\/j.arr.2022.101734","article-title":"Vascular dementia: a microglia\u2019s perspective","volume":"81","author":"Y Yang","year":"2022","journal-title":"Ageing Res Rev"},{"issue":"9","key":"pone.0356885.ref003","doi-asserted-by":"crossref","first-page":"651","DOI":"10.3390\/cells14090651","article-title":"Multipotent mesenchymal stem cell therapy for vascular dementia","volume":"14","author":"E-Y Kim","year":"2025","journal-title":"Cells"},{"key":"pone.0356885.ref004","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.neuropharm.2017.12.030","article-title":"The pathology and pathophysiology of vascular dementia","volume":"134","author":"RN Kalaria","year":"2018","journal-title":"Neuropharmacology"},{"key":"pone.0356885.ref005","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3389\/fnagi.2013.00017","article-title":"Pathology and pathogenesis of vascular cognitive impairment-a critical update","volume":"5","author":"KA Jellinger","year":"2013","journal-title":"Front Aging Neurosci"},{"issue":"25","key":"pone.0356885.ref006","first-page":"3326","article-title":"Vascular cognitive impairment and dementia: JACC scientific expert panel","volume":"73","author":"C Iadecola","year":"2019","journal-title":"J Am Coll Cardiol"},{"issue":"19","key":"pone.0356885.ref007","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1042\/CS20160727","article-title":"Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia","volume":"131","author":"J Duncombe","year":"2017","journal-title":"Clin Sci (Lond)"},{"issue":"24","key":"pone.0356885.ref008","doi-asserted-by":"crossref","first-page":"6176","DOI":"10.3390\/ijms20246176","article-title":"Animal models of chronic cerebral hypoperfusion: from mouse to primate","volume":"20","author":"K Washida","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"6","key":"pone.0356885.ref009","first-page":"347","article-title":"Chronic cerebral hypoperfusion in rats--experimental model of vascular dementia","volume":"113","author":"M Nanri","year":"1999","journal-title":"Nihon Yakurigaku Zasshi"},{"issue":"1","key":"pone.0356885.ref010","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.brainresrev.2007.01.003","article-title":"Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases","volume":"54","author":"E Farkas","year":"2007","journal-title":"Brain Res Rev"},{"issue":"9","key":"pone.0356885.ref011","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1523\/JNEUROSCI.3970-14.2015","article-title":"A novel mouse model of subcortical infarcts with dementia","volume":"35","author":"Y Hattori","year":"2015","journal-title":"J Neurosci"},{"issue":"6586","key":"pone.0356885.ref012","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"P Tsvetkov","year":"2022","journal-title":"Science"},{"key":"pone.0356885.ref013","doi-asserted-by":"crossref","first-page":"120603","DOI":"10.1016\/j.jep.2025.120603","article-title":"Macelignan, a lignan from Myristica fragrans Houtt., rescues mitochondrial homeostasis and prevents cognitive decline in vascular dementia by modulating the mTOR-Mitophagy axis","volume":"355","author":"Z Qi","year":"2026","journal-title":"J Ethnopharmacol"},{"key":"pone.0356885.ref014","doi-asserted-by":"crossref","first-page":"102214","DOI":"10.1016\/j.arr.2024.102214","article-title":"The mechanism of cuproptosis in Parkinson\u2019s disease","volume":"95","author":"M Huang","year":"2024","journal-title":"Ageing Res Rev"},{"issue":"3","key":"pone.0356885.ref015","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1016\/j.apsb.2022.09.023","article-title":"Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: suppression of neuroinflammation by blocking NF-\u03baB transcription regulation and activating cAMP\/CREB axis","volume":"13","author":"Q Zhou","year":"2023","journal-title":"Acta Pharm Sin B"},{"issue":"11","key":"pone.0356885.ref016","doi-asserted-by":"crossref","first-page":"5270","DOI":"10.1002\/ptr.8316","article-title":"Exploring the therapeutic implications of natural compounds modulating apoptosis in vascular dementia","volume":"38","author":"G Zhong","year":"2024","journal-title":"Phytother Res"},{"key":"pone.0356885.ref017","doi-asserted-by":"crossref","first-page":"127923","DOI":"10.1016\/j.ijbiomac.2023.127923","article-title":"Tanshinone IIA, the key compound in Salvia miltiorrhiza, improves cognitive impairment by upregulating A\u03b2-degrading enzymes in APP\/PS1 mice","volume":"254","author":"X-Q Liu","year":"2024","journal-title":"Int J Biol Macromol"},{"key":"pone.0356885.ref018","doi-asserted-by":"crossref","first-page":"111404","DOI":"10.1016\/j.biopha.2021.111404","article-title":"A comprehensive review of tanshinone IIA and its derivatives in fibrosis treatment","volume":"137","author":"Z Bi","year":"2021","journal-title":"Biomed Pharmacother"},{"issue":"1","key":"pone.0356885.ref019","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41597-023-02888-4","article-title":"An RNA-seq atlas of mouse brain areas during fasting and diet-induced obesity","volume":"11","author":"PV Todorov","year":"2024","journal-title":"Sci Data"},{"key":"pone.0356885.ref020","doi-asserted-by":"crossref","first-page":"120377","DOI":"10.1016\/j.jep.2025.120377","article-title":"The effects and mechanisms of Shibing Xingnao formula in enhancing hippocampal synaptic plasticity in rats with vascular dementia","volume":"353","author":"X Gao","year":"2025","journal-title":"J Ethnopharmacol"},{"issue":"8","key":"pone.0356885.ref021","doi-asserted-by":"crossref","first-page":"609","DOI":"10.3390\/cells14080609","article-title":"The role of oxidative stress and inflammation in the pathogenesis and treatment of vascular dementia","volume":"14","author":"AY Altahrawi","year":"2025","journal-title":"Cells"},{"issue":"2","key":"pone.0356885.ref022","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/s41419-023-05639-w","article-title":"Copper homeostasis and copper-induced cell death in the pathogenesis of cardiovascular disease and therapeutic strategies","volume":"14","author":"X Chen","year":"2023","journal-title":"Cell Death Dis"},{"issue":"23","key":"pone.0356885.ref023","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.3390\/cells13231962","article-title":"Vascular cognitive impairment-the molecular basis and potential influence of the gut microbiota on the pathological process","volume":"13","author":"P Olejnik","year":"2024","journal-title":"Cells"},{"issue":"1","key":"pone.0356885.ref024","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1111\/ejn.16370","article-title":"The physiological and pathophysiological roles of copper in the nervous system","volume":"60","author":"J Gale","year":"2024","journal-title":"Eur J Neurosci"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356885","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:31:46Z","timestamp":1787592706000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0356885"}},"subtitle":[],"editor":[{"given":"Vincenzo","family":"Lionetti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0356885","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]}}}