{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:51:32Z","timestamp":1791161492725,"version":"4.1.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program","doi-asserted-by":"publisher","award":["2022YFC2703900"],"award-info":[{"award-number":["2022YFC2703900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2021-I2M-1-034"],"award-info":[{"award-number":["2021-I2M-1-034"]}]},{"DOI":"10.13039\/501100008235","name":"PUMCH","doi-asserted-by":"publisher","award":["UBJ10405"],"award-info":[{"award-number":["UBJ10405"]}],"id":[{"id":"10.13039\/501100008235","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Independent Research Fund","award":["2025-I-ZD-004"],"award-info":[{"award-number":["2025-I-ZD-004"]}]},{"name":"Independent Research Fund","award":["2021ZD0201100"],"award-info":[{"award-number":["2021ZD0201100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regulators that integrate multiple inflammatory cascades remain poorly understood. Here, we investigated whether Bruton\u2019s tyrosine kinase (BTK), which integrates DNA-sensing and Toll-like receptor signals upstream of the cGAS\u2013STING\u2013NF-\u03baB cascade, serves as a key regulatory node in ALS pathogenesis.<\/jats:p>\n                  <jats:p>Public RNA sequencing datasets of motor neurons (MNs) and post-mortem tissues from ALS patients were utilized to identify BTK expression patterns. SOD1-mutant human induced pluripotent stem cells (hiPSC) were differentiated into MNs (hiPSC-MNs) and microglia (hiPSC-MGs). NF-\u03baB dysregulation was profiled by scRNA sequencing (hiPSC-MGs) and bulk RNA sequencing (hiPSC-MNs). DNA damage (\u03b3H2AX), inflammatory signalling (western blot\/ELISA) and phagocytosis (pH-rodo uptake) were quantified, and microglial-conditioned medium was tested for MN toxicity. Monocultures and MN\u2013MG co-cultures received zanubrutinib (3 \u00b5M, 12 h). SOD1-G93A mice were administered zanubrutinib (30 mg\/kg, daily) from 2.5 months; motor performance, survival, spinal histology and PI3K\u2013AKT\u2013mTOR activity were assessed after 2 months of treatment.<\/jats:p>\n                  <jats:p>ALS spinal cord and cortex tissues of patients, as well as SOD1-mutant hiPSC-MG and hiPSC-MNs, demonstrated elevated BTK phosphorylation with increased p-STING, p-TBK1 and nuclear NF-\u03baB accumulation. ALS hiPSC-MG exhibited inflammatory activation, NLRP3 induction and impaired phagocytosis, while ALS hiPSC-MNs showed DNA damage and caspase-3-mediated apoptosis. Conditioned medium from inflammatory MG amplified neuronal STING\u2013NF-\u03baB activity and apoptosis, demonstrating non-cell-autonomous toxicity. The STING inhibitor H-151 reduced neuronal p-STING\/p-TBK1\/NF-\u03baB and apoptosis, confirming pathway causality. Pharmacological BTK inhibition reduced DNA damage in ALS hiPSC-MNs by 61.4% (P &amp;lt; 0.05), restored phagocytosis in ALS hiPSC-MG to 87.2% of control levels (P &amp;lt; 0.01) and prevented neuronal apoptosis induced by microglial conditioned medium. In SOD1-G93A mice, BTK blockade extended median survival from 158 to 183 days (P &amp;lt; 0.01, log-rank test), improved motor function, and attenuated neuroinflammation while moderately rebalancing PI3K\u2013AKT\u2013mTOR signalling without impairing autophagy\u2013lysosome dynamics.<\/jats:p>\n                  <jats:p>We identify BTK as a critical upstream regulator of the dysregulated cGAS\u2013STING\u2013NF-\u03baB signalling axis characteristic of ALS pathogenesis. BTK orchestrates both cell-autonomous dysfunction in MNs and non-cell-autonomous toxicity through microglial activation, representing a convergent regulatory node that integrates multiple pathogenic pathways. These mechanistic insights provide a molecular framework for understanding ALS neuroinflammation and establish a rational basis for BTK-targeted therapeutic intervention in neurodegeneration.<\/jats:p>","DOI":"10.1093\/brain\/awag070","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T12:40:02Z","timestamp":1771418402000},"page":"3440-3456","source":"Crossref","is-referenced-by-count":2,"title":["BTK inhibition suppresses neuroinflammation and neurodegeneration in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4033-477X","authenticated-orcid":false,"given":"Qing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]},{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, PUMCH , 102602, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS & PUMC , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaojie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baodong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Qiu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, Neuroscience Center, National Human Brain Bank for Development and Function, Department of Human Anatomy, Histology and Embryology, CAMS & PUMC , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, Neuroscience Center, National Human Brain Bank for Development and Function, Department of Human Anatomy, Histology and Embryology, CAMS & PUMC , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, PUMCH , 102602, Beijing ,","place":["China"]},{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS & PUMC , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC) , 100050, Beijing ,","place":["China"]},{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, PUMCH , 102602, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, PUMCH , 102602, Beijing ,","place":["China"]},{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS & PUMC , 100050, Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"2026100419575953000_awag070-B1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0140-6736(22)01272-7","article-title":"Amyotrophic lateral sclerosis","volume":"400","author":"Feldman","year":"2022","journal-title":"Lancet"},{"key":"2026100419575953000_awag070-B2","doi-asserted-by":"crossref","first-page":"e075037","DOI":"10.1136\/bmj-2023-075037","article-title":"Advances in molecular 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