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Breast cancer brain metastasis (BCBM) poses a significant clinical challenge, with endothelial barrier dysfunction representing a critical yet poorly understood step in metastatic progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A physiologically relevant in vitro blood\u2012brain barrier (BBB) model was established to evaluate exosomal functions. Mechanistic investigations included qPCR and western blotting for miR-221-3p, along with protein expression profiling, immunofluorescence-based tight junction protein visualization, apoptosis detection via annexin V\/PI staining, EdU assays for proliferation quantification, and transendothelial migration assessments. To validate the underlying mechanism, ALIX\/HRS were silenced to inhibit exosome secretion, and miR-221-3p antagonists were applied. Clinical relevance was assessed by analyzing plasma miR-221-3p levels in breast cancer (BC) patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Highly invasive breast cancer-derived exosomal miR-221-3p induced glycolysis and lactic acid accumulation in brain microvascular endothelial cells by targeting the leukemia inhibitory factor receptor (LIFR), leading to endothelial barrier destruction and reduced tight junction protein expression. This significantly enhanced endothelial barrier permeability and tumor cell transendothelial migration capacity. Silencing ALIX\/HRS or antagonizing miR-221-3p markedly reversed these effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings indicate that BC can target LIFR in hCMEC\/D3 cells via exosomal miR-221-3p, thereby promoting glycolysis and inhibiting the expression of tight junction proteins, which facilitates tumor metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-025-07372-8","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T14:55:12Z","timestamp":1763736912000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tumor exosomal miR-221-3p induces glycolysis through the LIFR\/GLUT1 pathway to destroy the cerebral vascular endothelial cell barrier and promote breast cancer brain metastasis"],"prefix":"10.1186","volume":"23","author":[{"given":"Kaitao","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongru","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilong","family":"Hei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongxin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WenG","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuojun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"7372_CR1","doi-asserted-by":"crossref","unstructured":"Bai X, et al. 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Immediately following surgery, the patient specimens were preserved in liquid nitrogen and subsequently transferred to a \u221280 \u00b0C freezer for storage until needed. And the serum and cerebrospinal fluid were similarly tested as previously described. The Research Ethics Committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University approved all protocols and procedures, and informed consent was acquired from the patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1333"}}