{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:04:19Z","timestamp":1780380259930,"version":"3.54.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"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. Immunol."],"abstract":"\n Background<\/jats:title>\n Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy in which neural activity is implicated in tumor progression. Nevertheless, whether primary SCLC elicits systemic effects on the brain remains uncertain.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Using an\n Rb1\/Trp53\/Myc<\/jats:italic>\n -driven SCLC mouse model, we performed whole-brain single-nucleus RNA sequencing (n = 48,686 nuclei) integrated with transcriptomic and metabolomic analyses of lung tumors and plasma, validating our findings across public SCLC cohorts. Pharmacological inhibition of GABA\n A<\/jats:sub>\n receptors with flumazenil was also applied\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We observed widespread, cell-type-resolved transcriptional alterations across the brain in tumor-bearing mice.\n Gad2<\/jats:italic>\n expression broadly increased in basal ganglia cells and GABAergic inhibitory neurons. Concurrently, oligodendrocyte precursor cells exhibited impaired maturation, accompanied by coordinated downregulation of myelination-related genes (\n Mbp<\/jats:italic>\n ,\n Plp1<\/jats:italic>\n ,\n Mobp<\/jats:italic>\n ). Metabolomic analyses demonstrated significantly higher levels of glutamate and GABA in lung tumors from tumor-bearing mice relative to sham-treated controls. Clinical measurements indicated that glutamate and GABA were markedly increased in SCLC patient plasma, suggesting a systemic elevation of these neurotransmitters associated with tumor progression. Furthermore, pharmacological inhibition of GABA\n A<\/jats:sub>\n receptors with flumazenil significantly suppressed tumor growth\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Primary SCLC is associated with cell-type-specific brain transcriptional remodeling and elevated circulating glutamate, providing descriptive evidence for a lung\u2013brain metabolic axis. However, direct causal links within this axis remain to be established through future interventional studies.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1860628","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:41:27Z","timestamp":1780378887000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA sequencing"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingwei","family":"Duan","sequence":"first","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University","place":["Guangzhou, Guangdong, China"]},{"name":"National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Fu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkun","family":"Huo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal 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