{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:58:15Z","timestamp":1789138695556,"version":"build-2803163510"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"12","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018904","name":"Beijing Xisike Clinical Oncology Research Foundation","doi-asserted-by":"publisher","award":["Y\u2010Young2024\u20100374"],"award-info":[{"award-number":["Y\u2010Young2024\u20100374"]}],"id":[{"id":"10.13039\/100018904","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173177"],"award-info":[{"award-number":["82173177"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82303311"],"award-info":[{"award-number":["82303311"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82103429"],"award-info":[{"award-number":["82103429"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472955"],"award-info":[{"award-number":["82472955"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Communications"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Brain metastasis, a leading cause of death in patients with lung adenocarcinoma (LUAD), arises from tumor cells adapting to the unique microenvironment of the brain through metabolic remodeling regulated by key oncogenes. Here, we aimed to determine the role of high mobility group protein box 3 (HMGB3) in regulating tumor cell metabolism to promote the progression and brain metastasis of LUAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A LUAD cell model predisposed to brain metastasis was established, followed by differential gene expression analysis. HMGB3 expression was quantified via single\u2010cell RNA sequencing (scRNA\u2010seq) and immunohistochemistry, with clinical relevance assessed in two retrospective cohorts: the primary LUAD and the LUAD brain metastasis cohorts. Gene enrichment analysis of scRNA\u2010seq and bulk RNA\u2010seq data, along with Western blotting, were performed to identify HMGB3\u2010associated pathways. Co\u2010immunoprecipitation combined with mass spectrometry was used to detect HMGB3\u2010interacting proteins. Gain\u2010of\u2010function, loss\u2010of\u2010function and rescue experiments targeting HMGB3 downstream pathways were conducted in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HMGB3 expression was significantly elevated in both primary LUAD lesions and brain metastatic foci, and its upregulation was strongly associated with poor prognosis in LUAD patients, as well as in those with concomitant brain metastasis. HMGB3 enhanced the migration, invasion, and epithelial\u2010mesenchymal transition (EMT) capabilities of LUAD cells in vitro and promoted the development of brain metastasis in vivo. Mechanistically, HMGB3 recruited and interacted with single\u2010stranded DNA\u2010binding protein 1 (SSBP1), inducing its nuclear translocation and reprogramming mitochondrial metabolism. This process elevated cytoplasmic reactive oxygen species levels, which subsequently activated the phosphatidylinositol 3\u2010kinase\/protein kinase B (PI3K\u2010Akt) signaling pathway through downregulating phosphatase and tensin homolog (PTEN), ultimately promoting tumor cell proliferation, migration, invasion, and EMT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrated HMGB3 as a key regulator of the brain metastasis of LUAD, orchestrating tumor cells\u2019 metabolic adaptation to the brain microenvironment through modulation of mitochondrial metabolism, thereby offering potential therapeutic targets for LUAD brain metastases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.70075","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T07:14:54Z","timestamp":1762413294000},"page":"1676-1705","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["HMGB3 promotes brain metastasis of lung adenocarcinoma by recruiting SSBP1 for nuclear translocation to remodel mitochondrial metabolism"],"prefix":"10.34133","volume":"45","author":[{"given":"Huanhuan","family":"Cui","sequence":"first","affiliation":[{"name":"Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College Fudan University  Shanghai P. R. China"},{"name":"Department of Neurosurgery Fudan University Shanghai Cancer Center  Shanghai P. R. China"},{"name":"Department of Oncology Shanghai Medical College, Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuechao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Fudan University Shanghai Cancer Center  Shanghai P. R. China"},{"name":"Department of Oncology Shanghai Medical College, Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Fudan University Shanghai Cancer Center  Shanghai P. R. China"},{"name":"Department of Oncology Shanghai Medical College, Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Hao","sequence":"additional","affiliation":[{"name":"Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College Fudan University  Shanghai P. R. China"},{"name":"Department of Oncology Shanghai Medical College, Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingtao","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Fudan University Shanghai Cancer Center  Shanghai P. R. China"},{"name":"Department of Oncology Shanghai Medical College, Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changshuai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Fudan University Shanghai Cancer Center  Shanghai P. R. 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