{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T11:22:55Z","timestamp":1794050575452,"version":"4.8.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Neuroinflammation plays a dual role in the central nervous system, offering protection in acute phases but contributing to chronic damage in neurodegenerative diseases. Estrogen, traditionally recognized for its reproductive functions, exerts extensive neuroprotective effects by modulating neuroinflammatory processes across multiple levels. This review explores the actions of estrogen through its receptors in astrocytes, microglia, and neurons, emphasizing its regulation of signaling pathways such as PI3K\/Akt, NF-\u03baB, and WNT\/\n                    <jats:italic>\u03b2<\/jats:italic>\n                    -catenin. Estrogen also enhances mitochondrial function, promotes DNA repair, and interacts with the gut microbiota to influence systemic inflammation. Furthermore, sex-specific responses to 17\n                    <jats:italic>\u03b1<\/jats:italic>\n                    -estradiol highlight the importance of hormonal context. Together, these findings underscore estrogen\u2019s potential as a multifaceted modulator of neuroinflammation and provide insight for precision therapeutic strategies.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2025.1671552","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:29:37Z","timestamp":1756704577000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["The estrogen\u2013brain interface in neuroinflammation: a multidimensional mechanistic insight"],"prefix":"10.3389","volume":"17","author":[{"given":"Jie","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tie-Jun","family":"Xian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Jun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1347987","DOI":"10.3389\/fnagi.2024.1347987","article-title":"The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets","volume":"16","author":"Adamu","year":"2024","journal-title":"Front. Aging Neurosci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1111\/bcpt.14035","article-title":"Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: a focused review","volume":"135","author":"Arjmand","year":"2024","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12974-020-1715-x","article-title":"G-protein-coupled estrogen receptor activation upregulates interleukin-1 receptor antagonist in the hippocampus after global cerebral ischemia: implications for neuronal self-defense","volume":"17","author":"Bai","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1161\/STROKEAHA.122.036946","article-title":"Neuroinflammation, stroke, blood-brain barrier dysfunction, and imaging modalities","volume":"53","author":"Candelario-Jalil","year":"2022","journal-title":"Stroke"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1002\/em.22087","article-title":"Mechanisms of DNA damage, repair, and mutagenesis","volume":"58","author":"Chatterjee","year":"2017","journal-title":"Environ. Mol. Mutagen."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1093\/gerona\/glab216","article-title":"17-\u03b1-estradiol has sex-specific effects on neuroinflammation that are partly reversed by gonadectomy","volume":"77","author":"Debarba","year":"2022","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.jsbmb.2013.07.007","article-title":"17\u03b2-estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia","volume":"138","author":"Dietrich","year":"2013","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"105018","DOI":"10.1016\/j.neubiorev.2022.105018","article-title":"Protective effect of sex steroid hormones on morphological and cellular outcomes after neonatal hypoxia-ischemia: a meta-analysis of preclinical studies","volume":"145","author":"Dur\u00e1n-Carabali","year":"2023","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1007\/s11154-013-9263-7","article-title":"Estrogen, astrocytes and the neuroendocrine control of metabolism","volume":"14","author":"Fuente-Martin","year":"2013","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"968373","DOI":"10.3389\/fcell.2022.968373","article-title":"Estrogen signaling as a bridge between the nucleus and mitochondria in cardiovascular diseases","volume":"10","author":"Guajardo-Correa","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"3952","DOI":"10.7150\/thno.30814","article-title":"Non-classical estrogen signaling in ovarian cancer improves chemo-sensitivity and patients outcome","volume":"9","author":"Hao","year":"2019","journal-title":"Theranostics"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3390\/antiox8030069","article-title":"Mechanism of rapid nuclear factor-E2-related factor 2 (Nrf2) activation via membrane-associated estrogen receptors: roles of NADPH oxidase 1, neutral sphingomyelinase 2 and epidermal growth factor receptor (Egfr)","volume":"8","author":"Ishii","year":"2019","journal-title":"Antioxidants (Basel)"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.expneurol.2008.09.015","article-title":"Estrogen inhibits Fas-mediated apoptosis in experimental stroke","volume":"215","author":"Jia","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"631007","DOI":"10.3389\/fonc.2021.631007","article-title":"Non-genomic actions of estrogens on the DNA repair pathways are associated with chemotherapy resistance in breast Cancer","volume":"11","author":"Jim\u00e9nez-Salazar","year":"2021","journal-title":"Front. Oncol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1210\/en.2006-1137","article-title":"MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia","volume":"148","author":"Jover-Mengual","year":"2007","journal-title":"Endocrinology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"961","DOI":"10.3390\/life14080961","article-title":"The uncoupling effect of 17\u03b2-estradiol underlies the resilience of female-derived mitochondria to damage after experimental TBI","volume":"14","author":"Kalimon","year":"2024","journal-title":"Life (Basel)"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.mce.2014.01.010","article-title":"Astrocyte-derived growth factors and estrogen neuroprotection: role of transforming growth factor-\u03b1 in estrogen-induced upregulation of glutamate transporters in astrocytes","volume":"389","author":"Karki","year":"2014","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"892","DOI":"10.3390\/antiox10060892","article-title":"17-\u03b2 estradiol rescued immature rat brain against glutamate-induced oxidative stress and neurodegeneration via regulating Nrf2\/HO-1 and MAP-kinase signaling pathway","volume":"10","author":"Khan","year":"2021","journal-title":"Antioxidants (Basel)"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1002\/jcb.21936","article-title":"Estrogenic control of mitochondrial function and biogenesis","volume":"105","author":"Klinge","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"101435","DOI":"10.1016\/j.redox.2020.101435","article-title":"Estrogenic control of mitochondrial function","volume":"31","author":"Klinge","year":"2020","journal-title":"Redox Biol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"11416","DOI":"10.3390\/ijms252111416","article-title":"17\u03b2-estradiol abrogates TNF-\u03b1-induced human brain vascular Pericyte migration by downregulating miR-638 via ER-\u03b2","volume":"25","author":"Kurmann","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1002\/jnr.21564","article-title":"Mitochondrial nuclear receptors and transcription factors: who's minding the cell?","volume":"86","author":"Lee","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s12974-023-02889-5","article-title":"Supraphysiologic doses of 17\u03b2-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism","volume":"20","author":"Li","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"166","DOI":"10.4103\/ATN.ATN-D-24-00013","article-title":"Advanced technologies for the study of neuronal cross-organ regulation: a narrative review","volume":"1","author":"Lin","year":"2024","journal-title":"Adv. Technol. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"420","DOI":"10.3389\/fendo.2019.00420","article-title":"Estrogen promotes pro-resolving microglial behavior and phagocytic cell clearance through the actions of Annexin A1","volume":"10","author":"Loiola","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"21467","DOI":"10.1038\/srep21467","article-title":"Estrogen replacement therapy-induced neuroprotection against brain ischemia-reperfusion injury involves the activation of astrocytes via estrogen receptor \u03b2","volume":"6","author":"Ma","year":"2016","journal-title":"Sci. Rep."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1042\/EBC20200162","article-title":"Estrogen receptors and the aging brain","volume":"65","author":"Maioli","year":"2021","journal-title":"Essays Biochem."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"104008","DOI":"10.1016\/j.mcn.2025.104008","article-title":"Estradiol activates the CaMKK\u03b2\/AMPK pathway to enhance neurite outgrowth in cultured adult sensory neurons","volume":"133","author":"Mishra","year":"2025","journal-title":"Mol. Cell. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.molbrainres.2004.10.043","article-title":"Regulation of glutamate transporter GLAST and GLT-1 expression in astrocytes by estrogen","volume":"138","author":"Pawlak","year":"2005","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.neuroscience.2012.10.014","article-title":"Activity-dependent, stress-responsive BDNF signaling and the quest for optimal brain health and resilience throughout the lifespan","volume":"239","author":"Rothman","year":"2012","journal-title":"Neuroscience"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"100897","DOI":"10.1016\/j.yfrne.2020.100897","article-title":"Astroglial cells as neuroendocrine targets in forebrain development: implications for sex differences in psychiatric disease","volume":"60","author":"Rurak","year":"2021","journal-title":"Front. Neuroendocrinol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"100298","DOI":"10.1016\/j.coemr.2021.100298","article-title":"Glial estradiol synthesis after brain injury","volume":"21","author":"Saldanha","year":"2021","journal-title":"Curr Opin Endocr Metab Res"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.yfrne.2006.09.004","article-title":"Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS","volume":"27","author":"Scharfman","year":"2006","journal-title":"Front. Neuroendocrinol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"203881","DOI":"10.1016\/j.cdev.2023.203881","article-title":"17\u03b2-estradiol mitigates the inhibition of Sh-Sy5Y cell differentiation through Wnt1 expression","volume":"176","author":"Shakya","year":"2023","journal-title":"Cells Dev"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"eadx0043","DOI":"10.1126\/science.adx0043","article-title":"Neuroinflammation across neurological diseases","volume":"388","author":"Shi","year":"2025","journal-title":"Science"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.jsbmb.2015.02.013","article-title":"Inflammasomes are neuroprotective targets for sex steroids","volume":"153","author":"Slowik","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"682","DOI":"10.5009\/gnl18221","article-title":"Effects of 17\u03b2-estradiol on colonic permeability and inflammation in an Azoxymethane\/dextran sulfate sodium-induced colitis mouse model","volume":"12","author":"Song","year":"2018","journal-title":"Gut Liver"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s40035-024-00409-w","article-title":"Focusing on mitochondria in the brain: from biology to therapeutics","volume":"13","author":"Song","year":"2024","journal-title":"Transl Neurodegener"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"631552","DOI":"10.3389\/fcell.2021.631552","article-title":"The role of gut microbial \u03b2-Glucuronidase in estrogen reactivation and breast Cancer","volume":"9","author":"Sui","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.reth.2023.12.018","article-title":"Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human iPSC-derived neural models","volume":"25","author":"Supakul","year":"2024","journal-title":"Regen Ther"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"8309031","DOI":"10.1155\/2016\/8309031","article-title":"Nlrp3 Inflammasome activation in the brain after global cerebral ischemia and regulation by 17\u03b2-estradiol","volume":"2016","author":"Thakkar","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"4248526","DOI":"10.1155\/2018\/4248526","article-title":"17\u03b2-estradiol regulates microglia activation and polarization in the Hippocampus following global cerebral ischemia","volume":"2018","author":"Thakkar","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1007\/s10571-022-01301-9","article-title":"Involvement of the G-protein-coupled estrogen Receptor-1 (GPER) signaling pathway in neurodegenerative disorders: a review","volume":"43","author":"Upadhayay","year":"2023","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1093\/procel\/pwad026","article-title":"The microbiota-gut-brain axis and neurodevelopmental disorders","volume":"14","author":"Wang","year":"2023","journal-title":"Protein Cell"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/s41420-024-02273-z","article-title":"17\u03b2-estradiol alleviated ferroptotic neuroinflammation by suppressing ATF4 in mouse model of Parkinson's disease","volume":"10","author":"Wang","year":"2024","journal-title":"Cell Death Discov"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.brainres.2010.09.069","article-title":"Estrogen and aging affect the synaptic distribution of estrogen receptor \u03b2-immunoreactivity in the CA1 region of female rat hippocampus","volume":"1379","author":"Waters","year":"2011","journal-title":"Brain Res."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"4130","DOI":"10.1073\/pnas.0306948101","article-title":"Mitochondrial localization of estrogen receptor beta","volume":"101","author":"Yang","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"eadp0696","DOI":"10.1126\/sciadv.adp0696","article-title":"Identification of an ionic mechanism for ER\u03b1-mediated rapid excitation in neurons","volume":"10","author":"Yu","year":"2024","journal-title":"Sci. Adv."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1089\/neu.2008.0544","article-title":"Estrogen-induced Bcl-2 expression after spinal cord injury is mediated through phosphoinositide-3-kinase\/Akt-dependent CREB activation","volume":"25","author":"Yune","year":"2008","journal-title":"J. Neurotrauma"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"266","DOI":"10.20517\/jtgg.2021.58","article-title":"Estrogen and DNA damage modulate mRNA levels of genes involved in homologous recombination repair in estrogen-deprived cells","volume":"6","author":"Zach","year":"2022","journal-title":"J. Transl. Genet. Genom."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"pyae054","DOI":"10.1093\/ijnp\/pyae054","article-title":"17\u03b2-estradiol ameliorates postoperative cognitive dysfunction in aged mice via miR-138-5p\/SIRT1\/HMGB1 pathway","volume":"27","author":"Zhang","year":"2024","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"74","DOI":"10.3892\/ijmm.2022.5130","article-title":"Focus on the role of mitochondria in NLRP3 inflammasome activation: a prospective target for the treatment of ischemic stroke (review)","volume":"49","author":"Zhang","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1164258","DOI":"10.3389\/fimmu.2023.1164258","article-title":"Immunomodulatory role of estrogen in ischemic stroke: neuroinflammation and effect of sex","volume":"14","author":"Zhong","year":"2023","journal-title":"Front. Immunol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.neuroscience.2015.07.057","article-title":"17\u03b2-estradiol up-regulates Nrf2 via PI3K\/AKT and estrogen receptor signaling pathways to suppress light-induced degeneration in rat retina","volume":"304","author":"Zhu","year":"2015","journal-title":"Neuroscience"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"e81354","DOI":"10.7759\/cureus.81354","article-title":"Estrogen-gut-brain Axis: examining the role of combined Oral contraceptives on mental health through their impact on the gut microbiome","volume":"17","author":"Zim","year":"2025","journal-title":"Cureus"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1671552\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:29:38Z","timestamp":1756704578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1671552\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,1]]},"references-count":55,"alternative-id":["10.3389\/fnagi.2025.1671552"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1671552","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,1]]},"article-number":"1671552"}}